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HK1031382B - Spiroazabicyclic heterocyclic compounds, a method for producing the same and use thereof - Google Patents

Spiroazabicyclic heterocyclic compounds, a method for producing the same and use thereof Download PDF

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Publication number
HK1031382B
HK1031382B HK01102261.7A HK01102261A HK1031382B HK 1031382 B HK1031382 B HK 1031382B HK 01102261 A HK01102261 A HK 01102261A HK 1031382 B HK1031382 B HK 1031382B
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Hong Kong
Prior art keywords
azabicyclo
octane
furo
pyridine
spiro
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HK01102261.7A
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Chinese (zh)
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HK1031382A1 (en
Inventor
E‧菲利普斯
R‧马克
J‧马科尔
S‧塞穆斯
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阿斯特拉公司
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Priority claimed from SE9702746A external-priority patent/SE9702746D0/en
Priority claimed from SE9800977A external-priority patent/SE9800977D0/en
Application filed by 阿斯特拉公司 filed Critical 阿斯特拉公司
Priority claimed from PCT/SE1998/001364 external-priority patent/WO1999003859A1/en
Publication of HK1031382A1 publication Critical patent/HK1031382A1/en
Publication of HK1031382B publication Critical patent/HK1031382B/en

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Spiroazabicyclic heterocyclic compounds, preparation method and use thereof
Technical Field
The present 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. It is a further object of the present invention to provide active compounds which act as potent ligands for nicotinic acetylcholine receptors (nAChR's).
Background
The use of compounds that bind to nicotinic acetylcholine receptors in the treatment of diseases involving decreased 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) is described by McDonald et al (1995) at "nicotinic acetylcholine receptors: molecular biology, Chemistry and pharmacology ", Annual Reports in Medicinal Chemistry, chapter 5, volume 30, pages 41-50, Academic Press inc., San Diego, CA; and Williams et al (1994) at "neuronal nicotinic acetylcholine receptors", Drug News & Perspectives, Vol.7, p.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 toxic bamboo mat basic drugs that may be used for the treatment of Alzheimer's disease and other diseases.
1-azabicyclo [2.2.2] oct-3-yl N- (2-alkoxyphenyl) carbamates and their local analgesic activity are disclosed in Pharmazie, Vol.48, 465, 466 (1993). In Acta Pharm Suecica, 7, 239-246(1970) it is disclosed that an ortho-substituted N-phenylcarbamic acid 1-azabicyclo [2.2.2] oct-3-yl ester on the phenyl ring is a topical analgesic.
Furopyridines for controlling synaptic transmission are disclosed in WO 97/05139.
Disclosure of the invention
According to the present invention we have found compounds of formula I, or enantiomers and pharmaceutically acceptable salts thereof, as potent ligands of nicotinic acetylcholine receptors: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, H2Or F2(ii) a A is N or C (R)2) (ii) a G is N or C (R)3) (ii) a D is N or C (R)4) (ii) a Provided 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; r1Is hydrogen or C1-C4An alkyl group; r2、R3And R4Independently of each other hydrogen, halogen atoms, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3Or R is2And R3Or R3And R4May combine to form another six-membered aromatic ring containing 0-2 nitrogen atoms, sharing A and G or G and D, respectivelyA heteroaromatic ring, and may be independently substituted with 1-2 of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3，R5And R6Independently of each other is hydrogen, C1-C4Alkyl, C (O) R7、C(O)NHR8、C(O)OR9、SO2R10Or may together be (CH)2)jQ(CH2)kWherein Q is O, S, NR11Or a bond; j is 2 to 7; k is 0 to 2; r7、R8、R9、R10And R11Independently is C1-C4Alkyl, aryl or heteroaryl.
Unless otherwise indicated, C1-C4Alkyl here means straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, C3-C4The alkyl group may also be a cyclic alkyl group such as cyclopropyl and cyclobutyl.
Unless otherwise indicated, C1-C6Alkyl here means straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl or isohexyl, C3-C6The alkyl group may also be a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Unless otherwise indicated, C1-C4Alkoxy here means straight-chain or branched alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy.
Unless otherwise indicated, C2-C4Alkenyl here means alkenyl containing one or two double bonds, such as vinyl, isopropenyl, allyl,N-butenyl, isobutenyl, allyl, 1, 3-butadienyl.
Unless otherwise indicated, C2-C4Alkynyl here means alkynyl containing a triple bond, such as ethynyl, propynyl, 1-or 2-butynyl.
Halogen atom means here fluorine, chlorine, bromine or iodine.
Aryl means a phenyl ring optionally substituted with one to three of the following substituents, unless otherwise specified: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3；
Unless otherwise indicated, heteroaryl refers to a 5 or 6 membered aromatic ring containing one or two nitrogen atoms, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl or pyrazolyl, the carbon atoms on the ring being optionally substituted by one to three of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3；R5And R6May together be (CH)2)jQ(CH2)kWherein Q is O, S, NR11Or a bond, j is 2-7 (preferably 2-3) and k is 0-2, such that a 3-7 membered ring, preferably a 5-or 6-membered ring, is formed, for example a pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl group.
R2And R3May together form another six-membered aromatic or heteroaromatic ring containing 0-2 nitrogen atoms, sharing a and G, such as quinoline, 1, 5-naphthyridine, 1, 6-naphthyridine, 1, 7-naphthyridine or 1, 8-naphthyridine.
R3And R4May together form another group containing G and D in commonA six-membered aromatic or heteroaromatic ring having 0 to 2 nitrogen atoms, such as isoquinoline, 2, 5-naphthyridine, 2, 6-naphthyridine, 2, 7-naphthyridine or 2, 8-naphthyridine.
Preferred compounds of the invention are those of formula I wherein m is 1, n is 0, p is 0, X is oxygen, W is H2A is C (R)2) G is C (R)3) D is C (R)4)。
Preferred compounds of the invention include the following compounds and enantiomers thereof and pharmaceutically acceptable salts thereof: 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 ' - (benzenesulfonylamino) 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-formylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' -N-acetamidopiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] isoquinoline ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] quinoline ]; 5 ' -vinylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (E) - (styryl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (4-morpholino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (1-azetidinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (E) - (2- (4-pyridyl) vinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (E) - (2- (2-pyridyl) vinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (2-trimethylsilylethynyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' -ethynylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (2-furyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (3-pyridyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' -methyl spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine-5 ' carbonitrile ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine-5 ' carboxamide ]; 5 '-N' - (3-chlorophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] pyridine ]; 5 '-N' - (2-nitrophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] pyridine ]; 4 ' -chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -methoxyspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -thiophenylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' - (N-2-aminoethyl) aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -anilinospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -methylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' - (4-N-methylpiperazin-1-yl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [3, 2-c ] pyridine ]; 4 ' -chloro-spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [3, 2-c ] pyridine ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine-7 ' -oxide ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine-6 ' -carbonitrile ]; 6 ' -chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]; 6 ' -Fluorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ].
Particularly preferred compounds of the invention are those of formula I wherein m is 1, n is 0, p is 0, X is oxygen, W is H2A ═ CH, D ═ CH, and G ═ C (R)3) Comprising the following compounds: spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a Spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine-7' -oxide](ii) a 5' -Bromospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -Phenylspiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -Nitrospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (Phenylcarboxamido) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (Phenylaminocarbonylamino) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (Benzenesulfonylamino) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -Aminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -N-Methylaminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -N, N-Dimethylaminospiro [ 1-aza ]Bicyclo [2.2.2]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -N, N-diethylaminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -N-Ethylaminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -N-benzylaminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -N-formylaminospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -N-Acetaminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -Vinylspiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (E) - (styryl) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (4-Morpholino) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (1-azetidinyl) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (E) - (2- (4-pyridyl) vinyl) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (E) - (2- (2-pyridyl) vinyl) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (2-trimethylsilylethynyl) spiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -ethynylspiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (2-furyl) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' - (3-pyridinyl) spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5' -Methylspiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a Spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine-5' carbonitriles](ii) a Spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine-5' carboxamides](ii) a 5 '-N' - (3-chlorophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound](ii) a 5 '-N' - (2-nitrophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '- (3' H) -furo [2, 3-b]Pyridine compound]；
Preparation method
Unless otherwise indicated, A, G, D, X, W, Y, Z, m, n and p are as defined above for formula I in the following reaction schemes and text.
(A) Compounds wherein p is 0 and Y is N
According to the process shown in scheme I, compounds of formula I wherein p is 0 and Y is N can be prepared.
Procedure I (p ═ 0)
Deprotection of a compound of formula IIA with an acid in a suitable solvent may be prepared wherein W ═ H2And p is 0. Suitable acids include inorganic acids, organic acids, and lewis acids such as hydrochloric and hydrobromic acids, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, and boron trifluoride etherate. A preferred acid is hydrobromic acid. Suitable solvents include acetone, butanone, ethanone and pinacolone. The preferred solvent is acetone. The reaction is generally carried out at a temperature of from about-10 ℃ to about 100 ℃, preferably from about 0 ℃ to about 60 ℃. Or deprotected by heating the borane complex in an alcoholic solvent. The preferred method is refluxing an alcoholic solution of the complex.
Compounds of formula I wherein W ═ O (oxygen) and p is 0 can be prepared by oxidation of a compound of formula IIA, such as with selenium dioxide, or by reaction first with N-bromosuccinimide, then with sodium bicarbonate and dimethyl sulfoxide, followed by removal of the borane groups according to the methods described previously.
Compounds of formula I wherein W ═ F can be prepared from compounds of formula I wherein W ═ O by reaction with a fluorinating agent such as diethylaminosulfur trifluoride2And p is 0.
By reacting a compound of formula III (wherein L is fluorine, chlorine, bromine, iodine, -OCH) in an inert solvent in the presence of a base3、-SPh、-SCH3、-SO2Ph or-SO2CH3) Cyclization can prepare compounds of formula IIA. Suitable bases include sodium hydride, sodium amide, potassium hydride, potassium tert-amylate, potassium tert-butoxide, and potassium bis (trimethylsilyl) amide. The preferred base is sodium hydride. Suitable inert solvents include N, N-dimethylformamide, N-methylpyrrolidin-2-one, ethers such as diethyl ether and tetrahydrofuran, and 1, 4-dioxane and dimethyl sulfoxide. A preferred inert solvent is N, N-dimethylformamide. The reaction is generally carried out at a temperature of from about 10 ℃ to about 100 ℃, preferably from about 20 ℃ to about 66 ℃.
Compounds of formula III wherein L is fluorine, chlorine, bromine, iodine, -OCH, can be prepared by reacting a compound of formula IV with a compound of formula V wherein L is as defined above, in an inert solvent3、-SPh、-SCH3、-SO2Ph or-SO2CH3. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1, 4-dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of from about-100 ℃ to about 0 ℃, preferably from about-78 ℃ to about-25 ℃.
Compounds of the formula V, in which L is as defined above, can be prepared from compounds of the formula VIII, in which L is as defined above, using a lithium base and a proton-transfer agent in an inert solvent. Suitable lithium bases include lithium diisopropylamide, n-butyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium. The preferred lithium base is phenyl lithium. Suitable proton transfer agents include hindered secondary amines such as diisopropylamine and 2, 2, 6, 6-tetramethylpiperidine. The preferred proton transfer agent is diisopropylamine. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1, 4-dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of from about-100 ℃ to about 0 ℃, preferably from about-78 ℃ to about-25 ℃. The compound of formula V can generally be used directly without purification for reaction with the compound of formula IV.
By reacting a compound of formula VI with Borane (BH) in an inert solvent3Or B2H6) By reaction, the compound of formula IV can be prepared. Borane in tetrahydrofuran is preferred. Suitable inert solvents include diethyl ether, tetrahydrofuran and 14-dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of from about-10 ℃ to about 66 ℃, preferably from about 0 ℃ to about 20 ℃.
Compounds of formula VIII are known, e.g. commercially available or can be prepared by methods known to those skilled in the art (see e.g. chemistry of heterocyclic compounds, pyridine and its derivatives, first part, e.klingsberg.ed., Interscience Publishers, Inc, NY, 1960).
The compounds of formula VI can be prepared from compounds of formula VII according to methods known to those skilled in the art. For example, compounds of formula VI wherein X represents oxygen can be prepared from the corresponding compounds of formula VII wherein X represents oxygen of the ketone, using one of the art-known reagents for preparing ethylene oxide from ketones (see e.g., the reaction of J. March, "Advanced Organic chemistry" (1985) 3 rd edition, page 1161). Compounds of formula VI wherein X represents sulphur may be prepared from the corresponding compounds of formula VII wherein X represents oxygen or sulphur, using one of the methods well known in the art for the preparation of episulphides from ketones or thioketones (see e.g.the reaction described in J.March, "Advanced Organic Chemistry" (1985) 3 rd edition, page 866-867).
Compounds of formula VII are known, e.g. commercially available or may be prepared by methods known to those skilled in the art (see e.g. chemistry of heterocyclic compounds, heterocyclic ring systems with bridgehead nitrogen atoms, second part, w.l, mosby.ed., Interscience Publishers, Inc, NY, 1961).
(B) Compounds wherein p is 1 and Y is N
Compounds of formula I (where p ═ 1) can be prepared according to the procedures described in scheme II or scheme III below. Scheme II (p ═ 1)Scheme III
Deprotection of a compound of formula IX wherein W is H, with an acid in a suitable solvent may be prepared2And p is 1. Suitable acid packageIncluding inorganic, organic and lewis acids such as hydrochloric and hydrobromic acids, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid and boron trifluoride etherate. A preferred acid is hydrobromic acid. Suitable solvents include acetone, butanone, ethanone and pinacolone. The preferred solvent is acetone. The reaction is generally carried out at a temperature of from about-10 ℃ to about 100 ℃, preferably from about 0 ℃ to about 60 ℃. Or deprotected by heating the borane complex in an alcoholic solvent. The preferred method is refluxing an alcoholic solution of the complex.
By oxidation of a compound of formula I (wherein W is H)2And p is 1), a compound of formula I wherein W ═ O and p is 1 can be prepared, for example, by oxidation with selenium dioxide or by first reacting with N-bromosuccinimide, then with sodium bicarbonate and dimethyl sulfoxide, followed by removal of the borane groups according to the methods described previously.
Compounds of formula I wherein W ═ F can be prepared from compounds of formula I wherein W ═ O and p is 1 by reaction with diethylaminosulfur trifluoride2And p is 1.
By reacting a compound of formula X (wherein L is fluorine, chlorine, bromine, iodine, -OCH) in an inert solvent in the presence of a base3、-SPh、-SCH3、-SO2Ph or-SO2CH3) Cyclization can produce compounds of formula IX. Suitable bases include sodium hydride, sodium amide, potassium hydride, potassium tert-amylate, potassium tert-butoxide, and potassium bis (trimethylsilyl) amide. The preferred base is sodium hydride. Suitable inert solvents include N, N-dimethylformamide, N-methylpyrrolidin-2-one, ethers such as diethyl ether and tetrahydrofuran, and 1, 4-dioxane and dimethyl sulfoxide. A preferred inert solvent is N, N-dimethylformamide. The reaction is generally carried out at a temperature of from about-10 ℃ to about 100 ℃, preferably from about 20 ℃ to about 66 ℃.
Compounds of formula X wherein L is fluorine, chlorine, bromine, iodine, -OCH may be prepared by reacting a compound of formula XI with a compound of formula V wherein L is as defined above, in an inert solvent3、-SPh、-SCH3、-SO2CH3. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1, 4-Dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of from about-100 ℃ to about 0 ℃, preferably from about-78 ℃ to about-25 ℃.
In an inert solvent in an amine base such as triethylamine, dimethylaminopyridine or diazabicyclo [4.3.0 ]]Compound XI can be prepared by reacting compound XII, wherein P is-SO, with a reagent such as tosyl chloride, mesyl chloride or trifluormesyl fluoride in the presence of nonane2Ph、-SO2PhCH3-4、-SO2CH3or-SO2CF3. Suitable inert solvents may be dichloromethane, chloroform, tetrahydrofuran, diethyl ether or dioxane. A preferred inert solvent is dichloromethane. The reaction is generally carried out at a temperature of from about-10 ℃ to about 66 ℃, preferably from about 0 ℃ to about 20 ℃.
Compound XII can be prepared from compounds of formula XIII by reduction with a reagent such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium triethylboride or lithium triethylboride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, sodium tri-sec-butylborohydride or lithium borohydride. A preferred reagent is lithium borohydride. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1, 4-dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of from about-78 ℃ to about 66 ℃, preferably from about-10 ℃ to about 20 ℃.
By reacting a compound of formula XIV with a Borane (BH) in an inert solvent3Or B2H6) By reaction, a compound of formula XIII can be prepared, wherein R is C1-C6Alkyl, -CH2-Ar or Ar, wherein Ar is phenyl optionally substituted with 1 to 3 of the following substituents: halogen atom, C1-C4Alkyl or C1-C4An alkoxy group. Borane in tetrahydrofuran is preferred. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1, 4-dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of from about-10 ℃ to about 66 ℃, preferably from about 0 ℃ to about 20 ℃.
Compounds of formula XIV are known, e.g. from compounds of formula VII, as may be obtained commercially or by methods known to those skilled in the art for the preparation of beta-hydroxy esters by reaction of esters and ketones (see e.g. j. march, "advanced organic Chemistry" (1985) 3 rd edition, see reaction, page 439).
By reacting a compound of formula XVIII (wherein L is fluorine, bromine, iodine, -OCH) in an inert solvent in the presence of a base3、-SPh、-SCH3、-SO2Ph or-SO2CH3) Cyclization can produce compounds in which W is H2And p is 1. Suitable bases include sodium hydride, sodium amide, potassium hydride, potassium tert-amylate, potassium tert-butoxide, and potassium bis (trimethylsilyl) amide. The preferred base is sodium hydride. Suitable inert solvents include N, N-dimethylformamide, N-methylpyrrolidin-2-one, ethers such as diethyl ether and tetrahydrofuran, and 1, 4-dioxane and dimethyl sulfoxide. A preferred inert solvent is N, N-dimethylformamide. The reaction is generally carried out at a temperature of from about-10 ℃ to about 100 ℃, preferably from about 20 ℃ to about 66 ℃.
Compounds of formula XVIII, wherein L is as defined above, may be prepared by catalytic hydrogenation of a compound of formula XVII with a catalyst such as palladium on carbon, palladium on carbon hydroxide, palladium oxide, platinum on carbon, platinum oxide, Raney nickel or rhenium on carbon in an inert solvent. Suitable inert solvents include methanol, ethanol, aqueous methanol or ethanol, and ethyl acetate. The preferred solvent is ethanol. The reaction is generally carried out at a temperature of from about 0 ℃ to about 100 ℃, preferably from about 20 ℃ to about 50 ℃.
Compounds of formula XVII wherein L is as defined above may be prepared by reacting a compound of formula XV with a compound of formula XVI using a palladium catalyst and a suitable ligand, base and solvent. Suitable palladium catalysts include palladium acetate. Suitable ligands include phosphine ligands such as triphenylphosphine or tri-o-tolylphosphine. Suitable bases include amines and inorganic bases such as triethylamine, diisopropylethylamine, sodium carbonate or tetrabutylammonium acetate. Suitable solvents include dimethylformamide or acetonitrile. The reaction is generally carried out at a temperature of from about 0 ℃ to about 140 ℃, preferably from about 20 ℃ to about 85 ℃.
Compounds of formula XVI, wherein L is as defined above and R is as defined above, may be prepared according to literature procedures from commercially available starting materials2Is chlorine, bromine, iodine, fluorine, trifluoromethanesulfonyl, tosyl or mesyl.
The compounds of formula XV can be prepared from compounds of formula VII according to methods known to those skilled in the art for preparing allyl alcohols from ketones using vinyl metal salts such as vinyl magnesium bromide.
(C) Compounds in which p is 0 or 1
Compounds of formula I wherein R is hydrogen may be prepared from compounds of formula I wherein the corresponding substituent is hydrogen by reaction with a suitable halogenating agent, such as bromine in acetic acid2、R3Or R4A compound of formula I which is a halogen atom. The conversion may require the addition of an acidic catalyst, such as the corresponding iron trihalide.
By reaction with an appropriate alkyl, alkenyl, alkynyl, aryl or heteroaryl stannane reagent in the presence of an appropriate organometallic catalyst, such as tetrakis (triphenylphosphine) palladium (O), in an appropriate solvent, such as 1, 2-dimethoxyethane, to convert the corresponding substituent therein to a halogen atom or OSO2CF3Of the formula I wherein R2、R3Or R4Is C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl compounds of formula I.
By reaction with an aryl or heteroaryl boronic acid in the presence of a suitable organometallic catalyst, such as tetrakis (triphenylphosphine) palladium (O), in a suitable solvent, such as 1, 2-dimethoxyethane, from which the corresponding substituent is a halogen atom or OSO2CF3Of the formula I wherein R2、R3Or R4The compound of formula I is aryl or heteroaryl.
By nitration with a suitable nitrating agent, such as nitric acid in concentrated sulphuric acid, it is possible to remove compounds of the formula I in which the corresponding substituents are hydrogenCompounds preparation of Compounds of formula I, i.e. wherein R2、R3Or R4Is NO2A compound of formula I.
By appropriate methods, e.g. hydrogenation, from which the corresponding substituent is NO2Of the formula I wherein R2、R3Or R4Is NH2A compound of formula I. The hydrogenation may be carried out by reacting the compound dissolved in a suitable solvent with gaseous hydrogen in the presence of a suitable catalyst. Suitable solvents include methanol, ethanol and acetic acid. Suitable catalysts include palladium such as 10% palladium on carbon.
By a suitable alkylation process, from which the corresponding substituent is NHR5Of the formula I wherein R2、R3Or R4Is NR5R6(R6Is alkyl) are disclosed. By suitable alkylation processes, it is also possible to prepare the corresponding compounds from the group NH2Of the formula I wherein R2、R3Or R4Is NR5R6(wherein R is5And R6Are the same alkyl or R5And R6Together are (CH)2)jQ(CH2)k) A compound of formula I. Suitable alkylation methods include treatment with the appropriate alkyl halide or sulfonate and a base in an inert solvent such as DMF or with the appropriate aldehyde or ketone in the presence of an acid catalyst such as zinc chloride, a reducing agent such as sodium cyanoborohydride, and a solvent such as ethanol.
Compounds of formula I wherein R is OH, can be prepared from compounds of formula I wherein the corresponding substituent is OH by reaction with trifluoromethanesulfonic anhydride in a suitable solvent such as dichloromethane in the presence of a suitable base such as 2, 6-di-tert-butylpyridine2、R3Or R4Is OSO2CF3A compound of formula I.
By NHR with the appropriate amine5R6By substitution, it being possible for the corresponding substituents to be halides or OSO2CF3Of the formula I wherein R2、R3Or R4Is NR5R6A compound of formula I. Suitable methods include nucleophilic substitution (treatment with an amine in the presence of an excess or added base and a suitable solvent such as DMSO) or organometallic complex catalyzed substitution (treatment with an amine in the presence of a suitable organometallic complex such as a complex of palladium with a chelating phosphine ligand, as described in j.org.chem., 1996, volume 61, page 7240).
By suitable acylation methods from which the corresponding substituent is NH2Of the formula I wherein R2、R3Or R4Is NR5C(O)R7A compound of formula I. A suitable acylation process comprises the use of an acid chloride R in the presence of an optional nucleophilic catalyst, such as 4- (N, N-dimethylamino) pyridine, a base, such as pyridine or triethylamine, and a suitable solvent, such as tetrahydrofuran6C (O) Cl or by treatment with a carboxylic acid R in a suitable solvent, such as tetrahydrofuran6C (O) OH and a coupling reagent (e.g., 1, 3-dicyclohexylcarbodiimide).
In a suitable solvent, such as tetrahydrofuran, by reaction with a suitable isocyanate R8NCO treatment, from which the corresponding substituent is NHR5Of the formula I wherein R2、R3Or R4Is NR5C(O)NHR8A compound of formula I.
By treatment with an appropriate oxychloride or carbonate, optionally in the presence of a nucleophilic catalyst (e.g. 4- (N, N-dimethylamino) pyridine), a base (e.g. pyridine or triethylamine) and a suitable solvent (e.g. tetrahydrofuran), from which the corresponding substituent is NHR5Of the formula I wherein R2、R3Or R4Is NR5C(O)OR9A compound of formula I.
From which the corresponding substituent is NHR by treatment with a suitable sulfonyl chloride in a suitable solvent such as pyridine5Of the formula I wherein R2、R3Or R4Is NR5SO2R10A compound of formula I.
By reaction with cyanide salts in suitable solvents (possibly also with the addition of suitable catalysts), it is possible to obtain compounds from which the corresponding substituents are halide or OSO2CF3Of the formula I wherein R2、R3Or R4A compound of formula I being CN. Suitable cyanide salts include copper (I) cyanide, sodium or potassium dicyanocarboxylate, and suitable solvents include N, N-dimethylformamide, dimethyl sulfoxide or pyridine. Catalysts which contribute to this conversion include copper (I) oxide, tetrakis (triphenylphosphine) palladium (O) or nickel (O) complexes generated in situ from dibromobis (triphenylphosphine) nickel (ii), zinc and triphenylphosphine.
By an appropriately substituted 2-chloropyridine or by another substituent (e.g. by NH via a diazo intermediate)2Conversion of derivatives to OH derivatives) may be prepared wherein R2、R3Or R4Is OH, OC1-C4Alkyl group of the compounds of formula I.
If desired, hydroxyl, amino or other reactive Groups may be protected by Protecting Groups as described in standard textbook Greene and Wuts, protective Groups in organic Synthesis, 2 nd edition (1991).
Compounds of formula I can be prepared from other compounds of formula I using general methods of functional group interconversion known to those skilled in the art (see e.g. the reaction referred to in j. march, "Advanced Organic Chemistry" (1985) 3 rd edition).
Furthermore, several substituted compounds of formula I can be prepared with appropriately substituted compounds of formula VIII, i.e. R can be obtained from 2-chloro-5-trifluoromethylpyridine3Is CF3。
The above reaction is generally carried out at about 1 to about 3 atmospheres, preferably at ambient pressure (about 1 atmosphere), unless otherwise specified. The above reaction is carried out in an inert atmosphere, preferably under nitrogen, unless otherwise specified.
The compounds of the invention and intermediates can be isolated from their reaction mixtures according to standard techniques.
Acid addition salts of the compounds of formula I which may be mentioned include inorganic acid salts, such as hydrochloride and hydrobromide salts; and salts with organic acids such as formate, acetate, maleate, benzoate, tartrate and fumarate.
Acid addition salts of the compounds of formula I may be formed by reacting the free base or a salt, enantiomer or protected derivative thereof with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, such as water, dioxane, ethanol, tetrahydrofuran or diethyl ether or a mixture of solvents which may be removed by vacuum or freeze drying. The reaction is a metathesis process or may be carried out on an ion exchange resin.
The compounds of formula I may exist in tautomeric or enantiomeric forms, all such tautomers and enantiomers are included within the scope of the present invention. The various optical isomers can be obtained by separation of racemic mixtures of the compounds using conventional methods such as fractional crystallization or chiral HPLC. Or the individual enantiomers may be prepared by reacting the appropriate optically active starting materials under reaction conditions which do not cause racemization.
(D) Compounds in which Y is NO
Under appropriate conditions, such as sulfur dioxide ethanol solution at room temperature, by reduction reaction with an appropriate reducing agent, X is oxygen, A is C (R)2) G is C (R)3) And D is C (R)4) Is prepared from a compound of formula XIX wherein Y is NO, X is oxygen, A is C (R)2) G is C (R)3) And D is C (R)4) A compound of formula I.
By oxidation with a suitable oxidizing agent under suitable conditions (e.g., acetic acid solution of hydrogen peroxide at reflux temperature), a compound can be prepared from a compound in which Y is N, X is oxygen,A is C (R)2) G is C (R)3) And D is C (R)4) Compounds of formula I the compounds of formula XIX are prepared.
In a similar manner to the above-described parts (A), (B) and (C), a compound wherein Y is N, X is oxygen and A is C (R)2) G is C (R)3) And D is C (R)4) A compound of formula I.
Compounds of formula I wherein Y is N, A is C (R) can be prepared from compounds of formula I wherein Y is NO by rearrangement with a carboxylic anhydride (e.g. trifluoroacetic anhydride in DMF) in a suitable solvent2) (wherein R is2Is hydroxy) is provided.
By reaction with phosphorus halides or phosphorus oxyhalides, pure or with the addition of suitable cosolvents, e.g. pure phosphorus oxychloride, it is possible to obtain a catalyst composition from which Y is NO and A is C (R2) (wherein R is2Is hydrogen) to the preparation of compounds of formula I wherein Y is N and A is C (R)2) (wherein R is2Is a halogen atom).
By reaction with a suitable cyanide source, such as trimethylsilylcyanide, in a suitable solvent, such as acetonitrile, in the presence of a suitable base, such as triethylamine, a catalyst can be prepared wherein Y is NO and A is C (R)2) (wherein R is2Is hydrogen) to the preparation of compounds of formula I wherein Y is N and A is C (R)2) (wherein R is2CN) of formula I.
Intermediates
Another aspect of the invention relates to novel intermediates. Of particular interest among these novel intermediates are borane-containing compounds, particularly compounds of formula II in scheme I and compounds of formula XIII in scheme II. These intermediates may be used in the synthesis of compounds of formula I, but their use is not limited to the synthesis of said compounds.
Accordingly, we provide a compound of formula II or an enantiomer thereof:wherein n is 0 or 1; m is 0 or 1; p is 0 or 1; x is oxygen or sulfur; w is oxygen, H2Or F2(ii) a A is N or C (R)2)；G is N or C (R)3) (ii) a D is N or C (R)4) (ii) a Provided that no more than one of A, G and D is nitrogen; r1Is hydrogen or C1-C4An alkyl group; r2、R3And R4Independently of each other hydrogen, halogen atoms, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3Or R is2And R3Or R3And R4May combine to form another six-membered aromatic or heteroaromatic ring containing 0-2 nitrogen atoms, sharing a and G or G and D, respectively, and may be independently substituted with 1-2 of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3，R5And R6Independently of each other is hydrogen, C1-C4Alkyl, C (O) R7、C(O)NHR8、C(O)OR9、SO2R10Or may together be (CH)2)jQ(CH2)kWherein Q is O, S, NR11Or a bond; j is 2 to 7; k is 0 to 2; r7、R8、R9、R10And R11Independently is C1-C4Alkyl, aryl or heteroaryl.
A compound of formula XIII:wherein n is 0 or 1; m is 0 or 1; x is oxygen or sulfur; r1Is hydrogen or C1-C4An alkyl group; r is C1-C6Alkyl, -CH2-Ar or Ar;
ar is phenyl optionally substituted with one to three of the following substituents: halogen atom, C1-C4Alkyl or C1-C4An alkoxy group.
The intermediate compounds may also exist in enantiomeric form and may be used as purified enantiomers, racemates or mixtures.
Another aspect of the invention is the use of compounds of formulae IV, III, II, XIII, X and IX as intermediates in the synthesis of nicotinic acetylcholine receptor ligands.
Another aspect of the invention relates to the use of a compound of formula I wherein Y is NO as an intermediate. These intermediates may be used in the synthesis of compounds of formula I wherein Y is N, but their use is not limited to the synthesis of said compounds.
Pharmaceutical composition
Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of a disorder or disease in a mammal (preferably a human) caused by dysfunction of nicotinic acetylcholine receptor neurotransmission, as shown below, comprising an effective amount of a compound of formula I, its enantiomer or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of such disease or disorder, and a pharmaceutically acceptable inert carrier.
For the above mentioned uses, the dosage administered will, of course, vary with the compound used, the route of treatment and the treatment desired. In general, however, satisfactory results are obtained when the compounds of the invention are administered in a daily dose of from about 0.1mg to about 20mg per kg of animal body weight, preferably in divided doses administered 1-4 times daily or in sustained release form. For humans, a total daily dose is from 5mg to 1400mg, more preferably from 10mg to 100mg, and unit dosage forms suitable for oral administration include from 2mg to 1400mg of the compound in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
The compounds of formula I or their enantiomers and pharmaceutically acceptable salts thereof may be used as such or in the form of suitable pharmaceutical preparations for enteral or parenteral administration. According to a further aspect of the invention we provide a pharmaceutical composition comprising preferably less than 80%, more preferably less than 50% by weight of a compound of the invention and a pharmaceutically acceptable inert diluent or carrier.
Examples of diluents and carriers are:
-lactose, starch, talc, stearic acid for tablets and dragees; for capsules tartaric acid or lactose;
-for injection solutions water, alcohol, glycerol, vegetable oils; for suppositories, natural or hardened oils or waxes are included.
We also provide a process for preparing such a pharmaceutical composition which comprises mixing the components.
Applications of
Another aspect of the invention is the use of a compound of the invention, an enantiomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of one of the diseases or disorders mentioned below; a method of treating or preventing the above-mentioned diseases or disorders, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention or an enantiomer or a pharmaceutically acceptable salt thereof.
The compounds of the invention are nicotinic acetylcholine receptor agonists. While not being bound by any theory, it is believed that agonists of the α 7nAChR (nicotinic acetylcholine receptor) subtype may be useful in the treatment or prevention of psychotic or intellectual impairment disorders, and that they have advantages over compounds that are, or are also, agonists of the α 4nAChR subtype. Therefore, compounds that are selective for the α 7nAChR subtype are preferred. The compounds of the invention have been shown to be pharmaceutical, particularly useful in the treatment or prevention of psychotic disorders or intellectual impairment disorders. Examples of psychiatric disorders include schizophrenia, mania, manic depression, and anxiety. Examples of intellectual impairment disorders include Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, and attention deficit hyperactivity disorder. The compounds of the invention may also be useful as analgesics in the treatment of pain, including chronic pain, and in the treatment or prevention of the following diseases: parkinson's disease, Huntington's chorea, Tourette's syndrome, neurodegenerative diseases in which cholinergic synapses are lost. It is further indicated that the compounds may be used for the treatment or prevention of jetlag, for inducing smoking cessation, and for the treatment or prevention of nicotine addiction (including nicotine addiction caused by exposure to nicotine-containing products).
We also believe that the compounds according to the invention may be used in the treatment or prevention of ulcerative colitis.
Pharmacological agents
The pharmacological activity of the compounds of the invention was determined by the following assay.
Test A-determination of the affinity for the α 7nAChR subtype
125Binding of I-alpha-Bungarotoxin (BTX) to rat hippocampal membranes. Rat hippocampus was homogenized in 20 volumes of cold homogenization buffer (HB: concentration of fractions (mM): tris (hydroxymethyl) aminomethane 50; magnesium chloride 1; sodium chloride 120; potassium chloride 5; pH 7.4). The homogenate was centrifuged at 1000g for 5 minutes, the supernatant (save) was removed and the pellet re-extracted. The combined supernatants were centrifuged at 12000g for 20 min, washed and resuspended in HB. The membrane (30-80. mu.g) was contacted with 5nM [ alpha ], [125I]alpha-BTX, 1mg/mL BSA (bovine serum albumin), test drug and 2mM calcium chloride or 0.5mM EGTA [ ethylene glycol-bis (. beta. -aminoethyl ether)]Incubate for 2 hours, then filter through Whatman glass fiber filters (thickness C) and wash four times with a Brandel cell harvester. For low filter blanks (0.07% of total counts per minute), pretreatment of the filters for 3 hours with an aqueous solution of 1% (BSA/0.01% PEI (polyethylene diamine) was critical and nonspecific binding was recorded with 100. mu.M (-) -nicotine, with specific binding typically 75%.
Test B-determination of the affinity for the alpha 4nAChR subtype
[3H]- (-) -nicotine binding. A modification of the method described in Martino-Barrows and Kellar (Mol Pharm (1987) 31: 169-125I]Rat brain (cortex) as described in the alpha-BTX binding assayAnd hippocampus), centrifuged at 12000 Xg for 20 min, washed twice, and then suspended in HB containing 100. mu.M diisopropyl fluorophosphate. After 20 minutes at 4 ℃, the membrane (about 0.5mg) is brought into contact with 3nM [ alpha ], [ beta ], [ alpha ], [ beta3H]- (-) -nicotine, test drug, 1. mu.M atropine and either 2mM calcium chloride or 0.5mM EGTA were incubated for 1 hour and then filtered through Whatman glass fiber filters (thickness C, pretreated with 0.5% PEI for 1 hour) using a Brandel cell harvester. Nonspecific binding was recorded with 100 μ M carbamoylnicotine, and specific binding was typically 84%.
Analysis of binding data for assays A and B
IC was calculated using the non-linear curve fitting program ALLFIT (Delean A, Munson P J and Rodbard D (1977) am. J. physiol., 235: E97-E102)50Value and pseudo (pseudo) Hill correlation coefficient (n)H). The saturation curves were fitted to a one-site model (one sitemodel) using the nonlinear regression program ENZFITTER (Leatherbarrow, R.J. (1987)), each yielding a one-site model125alpha-BTX and [ alpha ], [ alpha ] -BTX3H]K of (-) -nicotinic ligandsDValues of 1.67 and 1.70 nM. KiThe values are estimated using the general Cheng-Prusoff equation:
Ki-[IC50]/((2+ ([ ligand ]))]/[KD])n)1/n-1) wherein when nHWhen < 1.5, a value of n ═ 1 is used; when n isHWhen n is not less than 1.5, a value of n-2 is used. Samples were assayed in triplicate, typically ± 5%. Determination of K with 6 or more drug concentrationsiThe value is obtained. In test A or test B, the compounds of the invention are binding affinities (K)i) Compounds below 1000nM, indicating that they are therapeutically active.
The compounds of the present invention have the advantage that they are less toxic, more potent, more durable in action, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties.
Examples
Commercially available reagents can be used without purification. Mass spectra were recorded using a Hewlett Packard 5988A or MicroMass Quattro-1 mass spectrometer and the parent molecular ions were expressed in m/z and relative abundance. The room temperature means 20-25 ℃.
Preparation 1
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2' -oxirane ] N-borane complexes
A mixture of trimethylsulfoxonium iodide (16.10g, 73.2mmol) and sodium hydride (60% in mineral oil, 3.00g, 75.0mmol) in anhydrous dimethyl sulfoxide dispersion was stirred at room temperature under nitrogen for 30 minutes. Quinin-3-one (7.05g, 56.3mmol) was then added in portions as a solid and the resulting mixture was stirred at 65-70 ℃ under nitrogen for 1 hour. The reaction mixture was cooled, water (200ml) was added, and the resultant solution was extracted with chloroform (3X 200 ml). The chloroform extracts were combined and re-extracted with water (3X 200 ml). The chloroform layer was then dried (magnesium sulfate), filtered and evaporated under reduced pressure to give spiro [ 1-azabicyclo [2.2.2] as a clear, colorless liquid]Octane-3, 2' -oxiranes](6.51g, 46.8mmol, 83%). Spiro [ 1-azabicyclo [2.2.2] with stirring at 0 deg.C]Octane-3, 2' -oxiranes]A solution of borane in tetrahydrofuran (1.0M, 38.1ml, 38.1mmol) in anhydrous tetrahydrofuran (100ml) was added dropwise and the resulting solution was stirred at 0 ℃ under nitrogen for 30 minutes. Brine (100ml) was carefully added to the above reaction solution, and the resultant aqueous mixture solution was extracted with ethyl acetate (2X 100 ml). The organic extracts were combined, dried (magnesium sulfate), filtered and evaporated under reduced pressure to give the title compound as a white solid (4.3g, 28.1mmol, 74%): electrospray MS 152([ M-H ]]+，15)。
Preparation 2
3- (2-chloropyridin-3-ylmethyl) -3-hydroxy-1-azabicyclo [2.2.2] octane N-borane complexes
Phenyl lithium (1.8M in cyclohexane/diethyl ether [ 7: 3 ] was added at-60 ℃ under nitrogen]167ml, 0.3mol, 3eq.) of the solution in (A) was added to anhydrous tetrahydrofuran through a catheterPyran (350 ml). Diisopropylamine (0.7ml, 5mmol) was then added dropwise followed by 2-chloropyridine (28.4ml, 0.3mol, 3eq) over 10 minutes. The resulting solution was stirred at-40 ℃ for 1.5 hours under nitrogen. Then cooling the solution to-60 ℃, and dropwise adding spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2' -oxiranes]A solution of the N-borane complex (15.3g, 0.1mol) in tetrahydrofuran (75 ml). The resulting reaction mixture was then stirred at-40 ℃ under nitrogen. After 3 hours, saturated sodium bicarbonate solution (150ml) was slowly added followed by water (400ml) and the resulting aqueous mixture was allowed to warm to room temperature. The layers were separated and the aqueous phase was extracted with ethyl acetate (3X 100 ml). The organic layers were combined, dried (magnesium sulfate), filtered and evaporated under reduced pressure. Subjecting to silica gel column chromatography with ethyl acetate/hexane [ 3: 2]]Elution afforded the title compound as a brown solid (17.5g, 65.6mmol, 66%): electrospray MS 269([ MH)]+Is composed of37Cl，10)，267([MH]+Is composed of35Cl，26)。
Preparation 2(b)
From 2.64g (17.8mmol) of 2, 4-dichloropyridine and 1.37g (8.95mmol) of spiro [ 1-azabicyclo [2.2.2] octane-3, 2' -oxirane ] was prepared 3- (2, 4-dichloropyridin-3-ylmethyl) -3-hydroxy-1-azabicyclo [2.2.2] octane N-borane complex to give 2.42g (90%) m.p.178-179 deg.C (1: 1 ethyl acetate-hexane).
Preparation 3
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] pyridine ] N-borane complexes
Reacting 3- (2-chloropyridin-3-ylmethyl) -3-hydroxy-1-azabicyclo [2.2.2]Octane N-borane complex (17.4g, 65.3mmol) was dissolved in anhydrous N, N-dimethylformamide (500ml), the resulting solution was cooled to 0 ℃ under nitrogen, and sodium hydride dispersion (60% in mineral oil, 163mmol, 2.5eq) was added dropwise. The resulting solution was stirred at room temperature under nitrogen for 16 hours. Then, a saturated ammonium chloride solution (50ml) was added at 0 ℃ followed by ice water (500ml), and the resultant aqueous mixture was extracted with chloroform (4X 125 ml). The organic layers were combined, dried (magnesium sulfate),evaporation under reduced pressure gave an orange solid. Purifying with short silica gel column chromatography, and purifying with chloroform/acetone [ 95: 5-85: 15 ]]Elution, followed by stirring in hexanes (100ml) and filtration, gave the title compound as a yellow solid (12.7g, 55.2mmol, 84%): electrospray MS 231([ MH)]+，65)。
Preparation 4
3- (2-methanesulfonyloxyethyl) -3-trimethylsilyloxy-1-azabicyclo [2.2.2] octane N-borane complex
(a)2- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-yl) acetic acid tert-butyl ester
To a solution of diisopropylamine (6.7ml) in Tetrahydrofuran (THF) (20ml) was added n-butyllithium (2.3M in hexane, 20ml) at 0 ℃. The reaction mixture was stirred for 40 minutes and then cooled to-78 ℃. To the mixture was added dropwise a solution of tert-butyl acetate (6.4ml) in THF (10ml), and stirring was continued for 15 minutes. To this mixture was added dropwise a solution of quinin-3-one (5g) in THF (15ml) and the mixture was warmed to 0 ℃ over 1 hour. To this solution was added water (100ml), the solution was extracted twice with chloroform, and the combined extracts were washed once with brine. The resulting solution was dried over magnesium sulfate, filtered and evaporated in vacuo to give 9.53g of the sub-title compound as an off-white solid.
(b)2- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-yl) acetic acid methyl ester
Trifluoroacetic acid (40ml) was added dropwise to a solution of tert-butyl 2- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-yl) acetate (15.7g) in anhydrous dichloromethane (40ml) at 0 ℃ over 15 minutes. The mixture was stirred at room temperature for 24 hours, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (90ml) and cooled on an ice bath. Concentrated sulfuric acid (9ml) was added dropwise over 10 minutes, and the reaction mixture was stirred at room temperature. After 3 hours, the solution was poured into 100ml of ice water, basified to pH 10 with saturated aqueous sodium carbonate solution and extracted with chloroform (4X 100 ml). The extract was dried (magnesium sulfate), filtered and evaporated in vacuo to give a solid. Recrystallization from ethyl acetate gave 6.3g of the sub-title compound as brown crystals.
(c)2- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-yl) acetic acid methyl ester N-borane complex
Borane in THF (1M, 5.25ml) was added dropwise to a solution of methyl 2- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-yl) acetate (1g) in anhydrous Tetrahydrofuran (THF) (20ml) over 20 minutes with stirring at 0 ℃. After 30 minutes, 20ml of brine were added, stirring was continued for 30 minutes, and then the layers were separated. The aqueous layer was extracted with ethyl acetate (2X 20ml) and the organic layers were combined, then dried (magnesium sulfate), filtered and evaporated under reduced pressure. The residue was flash chromatographed on silica gel (eluting with chloroform/acetone, 95: 5) to give the title compound as an off-white solid (900 mg).
(d) 3-hydroxy-3- (2-hydroxyethyl) -1-azabicyclo [2.2.2] octane N-borane complexes
Lithium borohydride (2M in tetrahydrofuran, 2.6ml, 5.2mmol) was added to a solution of methyl 2- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-yl) acetate, N-borane complex (1g, 4.7mmol) in anhydrous tetrahydrofuran (20ml) under argon over 5 minutes and heated at reflux for 1 hour. The reaction was cooled (ice bath), quenched with water (5ml) and saturated aqueous sodium bicarbonate (5ml), stirred at 0 ℃ to room temperature for 45 minutes, and extracted four times with ethyl acetate. The combined organic layers were dried (magnesium sulfate), evaporated under reduced pressure and triturated with ether to give the title compound as a white solid (830mg, 4.5mmol, 95%).
(e) 3-trimethylsiloxy-3- (2-trimethylsiloxyethyl) -1-azabicyclo [2.2.2] octane N-borane complexes
Chlorotrimethylsilane (0.255ml, 2mmol) was added by syringe to a solution of 3-hydroxy-3- (2-hydroxyethyl) -1-azabicyclo [2.2.2] octane N-borane complex (185mg, 1mmol) in anhydrous 1-methylimidazole (1ml) at 0 ℃ under argon for 5 minutes. N- (trimethylsilyl) acetamide (262mg, 2mmol) was added in one portion and the reaction stirred at room temperature for 16 h and heated at 55-60 ℃ for 3 h. The mixture was cooled, poured onto ice/water (5g) and extracted four times with ether. The combined organic layers were washed four times with brine, dried (magnesium sulfate), evaporated under reduced pressure and purified by flash chromatography (eluting with hexane/ethyl acetate 3: 2) to give the title compound (210mg, 0.64mmol, 64%).
(f)3- (2-hydroxyethyl) -3-trimethylsilyloxy-1-azabicyclo [2.2.2] octane N-borane complexes
A solution of 3-trimethylsiloxy-3- (2-trimethylsiloxyethyl) -1-azabicyclo [2.2.2] octane N-borane complex (190mg, 0.58mmol) in anhydrous methanol (1ml, 0.25ml containing 0.032M potassium carbonate methanol) was stirred at room temperature under an argon atmosphere for 84 hours, acidified with acetic acid to pH 7, and evaporated under reduced pressure. Purification by flash chromatography (eluting with hexane/ethyl acetate 3: 2) gave the title compound (94mg, 0.37mmol, 63%).
(g)3- (2-methanesulfonyloxyethyl) -3-trimethylsilyloxy-1-azabicyclo [2.2.2] octane N-borane complex
A solution of methanesulfonyl chloride (0.086ml, 1.1mmol) in anhydrous pyridine (1ml) was added to a solution of 3- (2-hydroxyethyl) -3-trimethylsiloxy-1-azabicyclo [2.2.2] octane N-borane complex (257mg, 1mmol) in anhydrous pyridine (4ml) at 0 ℃ to 5 ℃ under an argon atmosphere for 20 minutes, followed by stirring at 0 ℃ for 20 minutes and at room temperature for 2 hours. Poured into ice (15g), extracted four times with ethyl acetate, the organic layers were combined and washed successively with 1N aqueous hydrochloric acid (three times), water and saturated aqueous sodium bicarbonate. The extract was dried (magnesium sulfate), evaporated under reduced pressure and purified by flash chromatography (eluting with chloroform/ethyl acetate 97: 3) to give the title compound (263mg, 0.78mmol, 78%).
Preparation 5
(a) 3-vinyl-3-hydroxy-1-azabicyclo [2.2.2] octane
A solution of 3-quinuclidinone (1.25g, 10mmol) in dry tetrahydrofuran (10ml) was added to a solution of 1M vinylmagnesium bromide in tetrahydrofuran (20ml, 20mmol) at 0 deg.C-5 deg.C under argon for 15 minutes, stirred at room temperature for 24 hours, cooled to 0 deg.C and acidified to pH 1 with 6M hydrochloric acid. The mixture was stirred for 15 min, basified to pH 10 with 25% aqueous sodium hydroxide, extracted with chloroform (4X 50ml) and chloroform/methanol (4: 1, 50ml), the organic layers combined, dried (magnesium sulfate), evaporated under reduced pressure and purified by flash chromatography (eluting with ammoniated chloroform/methanol 85: 15) to give the title compound (830mg, 5.4mmol, 54%).
(b) 3-bromo-2-hydroxypyridine
A solution of bromine (9.6g, 60mmol) in 1M aqueous potassium bromide (120ml) was added to a solution of 2-hydroxypyridine (5.7g, 60mmol) in 1M aqueous potassium bromide (60ml) over 5 minutes and stirred for 24 hours. The solid precipitate was filtered off, the aqueous phase was saturated with sodium chloride, extracted with chloroform (4X 20ml), and the combined extracts were dried (magnesium sulfate), evaporated under reduced pressure and combined with the previous precipitate. Purification by flash chromatography (eluting with ammoniated chloroform/methanol 95: 5) and recrystallisation from acetonitrile gave the title compound (3.62g, 20.8mmol, 35%).
(c) 3-bromo-2-methoxypyridine
A mixture of 3-bromo-2-hydroxypyridine (3.49g, 20mmol), silver carbonate (3.67g, 13.31mmol) and methyl iodide (1.5ml, 24.1mmol) in benzene (30ml) was stirred at 40 ℃ to 50 ℃ under argon atmosphere in the dark for 24 h, cooled on an ice bath and filtered. Washed once with 2% aqueous sodium bicarbonate, twice with water, dried (magnesium sulfate), benzene evaporated at atmospheric pressure and the residue purified by flash chromatography (eluting with hexane/ethyl acetate 2: 1) to give the title compound (2.35g, 12.5mmol, 62%).
Example 1
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] pyridine ]
Reacting 5' -spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]The N-borane complex (12.2g, 53mmol) was dissolved in 150ml of acetone, the solution was cooled to 0 ℃ and aqueous HBr (24%, 50ml) was added. The resulting solution was stirred at room temperature under nitrogen for 24 hours. The reaction was concentrated under reduced pressure and the aqueous residue was treated with saturated aqueous sodium bicarbonate (50 ml). By solidsThe solution was basified to pH > 10 with sodium carbonate and the resulting solution was extracted with chloroform (3X 100 ml). The organic extracts were combined, dried (magnesium sulfate), filtered and evaporated under reduced pressure to give the title compound as an off-white solid (11.2g, 51.8mmol, 98%, 54% total): electrospray MS 217([ MH)]+，72)。
The title compound was isolated as its (R) -and (S) -enantiomers by one of the following methods:
the method A comprises the following steps: 250mg of the above title compound was separated by chiral HPLC on a Waters Delta Prep 3000 preparative chromatography system using a 2 cm. times.25 cm CHIRALCEL-OD column eluting with 2, 2, 4-trimethylpentane/ethanol (98: 8-9: 1) at a flow rate of 20 ml/ml. 111g of the (S) -enantiomer ([ alpha ] is obtained]2359.7 ° (c ═ 1, methanol)) and 90mg of (r) -enantiomer ([ α)]23-63.9 ° (c-1, methanol)).
The method B comprises the following steps: 1g (4.62g) of the above title compound was treated with L- (+) -tartaric acid (694mg, 4.62mmol) in 15% aqueous ethanol (10ml) and recrystallized three times to give (S) -enantiomer L- (+) -tartrate salt (650mg, 1.77 mmol; [ alpha.;, [ alpha.; alpha.), (L- (+) -tartrate)]23+57.7 ° (c-2, water)). The filtrate was concentrated under reduced pressure and the aqueous residue was basified with solid sodium carbonate to a pH > 10. The resulting mixture was extracted with chloroform (3X 25ml), and the combined extracts were dried (magnesium sulfate) and evaporated under reduced pressure. The residue (650mg, 3mmol) was treated with D- (-) -tartaric acid (452mg, 3mmol) and recrystallized as described above to give (R) -enantiomer D- (-) -tartrate (775mg, 2.11 mmol; [ alpha ]; (a)]23-58.2 ° (c-2, water)).
Example 2A
5 ' -Bromospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Spiro [ 1-azabicyclo [2.2.2] s]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A solution of (100mg, 0.462mmol) and sodium acetate (410mg, 5mmol) in 50% aqueous acetic acid (4ml) was heated to 60 ℃. Bromine (0.100ml, 1.94mmol) was added via syringe over 10 minutes and the solution was then heated at reflux for 1 hour. The mixture was allowed to cool to room temperature,basified with sodium carbonate to pH > 10 and extracted with chloroform (3X 15 ml). The combined extracts were dried (sodium sulfate), filtered and evaporated under reduced pressure to give the title compound as an off-white solid (110mg, 0.37mmol, 81%): electrospray MS 295([ MH)]+Is composed of79Br 100)，297([MH]+Is composed of81Br98)。
Example 2B
(R) - (-) -5 ' -Bromospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
(R) - (-) -spiro [ 1-azabicyclo [2.2.2] was treated in the same manner as described in example 2A]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](1.95g, 9mmol) to give the title compound (1.77g, 6mmol, 67%) ([ alpha ] -c]23-45.5 ° (c-1, methanol)).
Example 3
5 ' -Phenylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
5' -Bromospiro [ 1-azabicyclo [2.2.2] 2 in a solution of 1, 2-dimethoxyethane (3ml) and ethanol (0.75ml) containing 2M aqueous sodium carbonate (0.65ml, 1.3mmol) was stirred under nitrogen]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](118mg, 0.4mmol), phenylboronic acid (54mg, 0.443mmol), and tetrakis (triphenylphosphine) palladium (O) (11mg, 2.3% (mol)). The mixture was heated at reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure, the residue was dissolved in chloroform (15ml), and the extract was washed with a saturated aqueous solution of sodium carbonate (5 ml). The aqueous layer was extracted with chloroform (2X 15ml) and the organic layers were combined, dried (magnesium sulfate), filtered and evaporated under reduced pressure. Purification by flash chromatography on silica gel eluting with ammoniated chloroform/methanol (95: 5-9: 1) gave the title compound as a brown solid (80mg, 0.274mmol, 68%): electrospray MS 293([ MH)]+，100)。
Example 4A
5 ' -Nitrospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Spiro [ 1-azabicyclo [2.2.2] at 70-80 deg.C]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A mixture of (325mg, 1.5mmol) and fuming nitric acid (0.27ml, 5.74mmol) in sulfuric acid (0.75ml) was heated for 24 hours. The resulting viscous solution was poured into 15g of ice and basified with solid sodium carbonate to pH > 10. The resulting mixture was extracted with chloroform (4X 15ml), dried (magnesium sulfate), filtered and evaporated under reduced pressure. Purification by flash chromatography on silica gel eluting with ammoniated chloroform/methanol (95: 5) gave the title compound as a pale yellow solid (200mg, 0.765mmol, 51%): electrospray MS 262([ MH)]+，100)。
Example 4B
(R) - (-) -5 ' -Nitrospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
(R) - (-) -spiro [ 1-azabicyclo [2.2.2] at 0 deg.C-5 deg.C]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](3.03g, 14mmol) was dissolved in concentrated sulfuric acid (7ml), fuming nitric acid (3.3ml, 70.2mmol) was added over 10 minutes, the mixture was stirred for 1 hour, and heated at 65 ℃ to 70 ℃ for 24 hours. Cool, pour into ice (200g), add 300ml water, basify to pH 10 with solid potassium carbonate, stir for 1 hour, filter and dry the solid title compound (3.6g, 13.8mmol, 98%): electrospray MS (m/z, relative abundance) 262([ MH)]+，100)。
Example 4C
(S) - (+) -5 ' -Nitrospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
(S) - (+) -Spiro [ 1-azabicyclo [2.2.2] treatment in the same manner as described in example 4B]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](6.5g, 30mmol) to give the title compound (7.75g, 29.7mmol, 99%): electrospray MS (m/z, relative abundance) 262([ MH)]+，100)。
Example 5
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] quinoline ]
According to an analogous method to that described in example 1, starting from 2-chloroquinoline (0.99g, 6.06mmol) and spiro [ 1-azabicyclo [2.2.2] e]Octane-3, 2' -oxiranes]N-borane Complex (0.31g, 2.0mmol) the title compound was prepared as a beige powder (0.135g), electrospray MS 267[ MH ]]+
The two enantiomers were resolved on a Chiral OD column, eluted with a 8-10% ethanol/hexane gradient and detected by UV. First enantiomer: chiral purity 100% by LC, [ alpha ] in ethanol at 23 ℃ for 12.32 min]D+47.9 °. The second enantiomer: 99.4% chiral purity. Rt 17.84 min, [ α [ ]]D＝-48.5°。
Example 6
1 ' -Chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] isoquinoline ]
According to a similar method to that described in example 1, starting from 1, 3-dichloroisoquinoline (2.41g, 12.2mmol) and spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2' -oxiranes]N-borane Complex (0.62g, 4.05mmol) the title compound was prepared to yield 0.86g of 1' -chlorospiro [ 1-azabicyclo [2.2.2] 2]Octane-3, 2 '(3' H) -furo [2, 3-b]Isoquinoline derivatives]N-borane complexes, electrospray MS 314[ MH]+. Removal of the boryl group from 65mg of N-borane complex gave 30mg of the title compound, electrospray MS 301[ MH]+。
Example 7
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] isoquinoline ]
Borane-protected chloride from example 6 (0.3g or 0.96mmol) was suspended in a mixture of glacial acetic acid (6.0ml) and water (0.5 ml). The suspension was placed under nitrogen and zinc powder (150mg) was added. The reaction mixture was stirred at 70 ℃ for 5 hours. The reaction mixture was allowed to cool and then poured into saturated sodium bicarbonate. Adding sufficient sodium bicarbonate to obtain alkalinepH, the product was extracted with three portions of chloroform. The combined chloroform extracts were dried (magnesium sulfate), filtered and evaporated in vacuo. The two batches were combined and purified by flash column chromatography on silica gel eluting with a gradient of 2: 1 hexane/ethyl acetate to 100% ethyl acetate. The faster eluting compound is spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Isoquinoline derivatives]The N-borane complex, the slower eluting compound, is the title compound. Yield 100%: the chemically ionized N-borane compound is MS 279[ MH]+-H2The title compound is 267[ MH]+. Removal of the borane groups under the conditions of example 1, followed by flash chromatography, gave the title compound as a brown semisolid: chemical ionization MS 267 MH]+。
Example 8A
5 ' -Aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Reacting 5' -Nitrospiro [ 1-azabicyclo [2.2.2] under 50psi of hydrogen]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A mixture of (1.4g, 5.36mmol) and 10% palladium on charcoal (48% wet weight with water, 270ml) in methanol (90ml) was hydrogenated for 1 hour. The catalyst was removed by filtration through celite and the solvent evaporated under reduced pressure to give the amine as a brown solid (1.2g, 5.25mmol, 98%): electrospray MS (m/z, relative abundance) 232([ MH)]+，100)。
The title compound was isolated as its (R) -and (S) -enantiomers by the following method:
150mg of the above title compound was separated by chiral HPLC on a Waters Delta Prep 4000 preparative chromatography system using a 2 cm. times.25 cm CHIRALCEL-OD column eluting with hexane/ethanol (85: 15-8: 2) at a flow rate of 20 ml/ml. 52mg of the (S) -epimer ([ alpha ] was obtained]22+62 ° (c ═ 1, ethanol)) and 52mg of (r) -epimer ([ α [)]23-64 ° (c ═ 1, ethanol)).
Example 8B
(R) - (-) -5 ' -aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
The enantiomer (R) - (-) -5' -Nitrospiro [ 1-azabicyclo [2.2.2] was treated in the same manner as described in example 8A]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](3.8g, 13.3mmol) and purified by flash chromatography (eluting with ammoniated chloroform/methanol 95: 5 to 85: 15) to give the title compound (2.5g, 10.8mmol, 81%): electrospray MS (m/z, relative abundance) 232([ MH)]+，100)。
Example 8C
(S) - (+) -5 ' -aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
The enantiomer (S) - (+) -5' -Nitrospiro [ 1-azabicyclo [2.2.2] in ammoniated methanol was treated in the same manner as described in example 8A]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](6.85g, 26.2mmol) to give the title compound (5.55g, 24mmol, 92%): electrospray MS (m/z, relative abundance) 232([ MH)]+，100)。
Example 9
5 ' -Phenylcarboxamidospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Benzoic acid (67mg, 0.55mmol), O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate ("TBTU" 176mg, 0.55mmol), 1-hydroxybenzotriazole hydrate ("HOBT", 78mg, 0.55mmol) and diisopropylethylamine (0.193ml, 1.1mmol) were mixed in dry N, N-dimethylformamide (8ml) under nitrogen and stirred for 10 min. Adding solid 5' -aminospiro [ 1-azabicyclo [2.2.2] in one step]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](115mg, 0.5mmol) and stirring was continued for 3 days. The solvent was evaporated under high vacuum at 55 ℃ and the residue partitioned between saturated aqueous sodium carbonate (2ml) and dichloromethane (10 ml). After separation, the aqueous layer was extracted with dichloromethane (2X 5 ml). The organic layers were combined, dried (magnesium sulfate) and evaporated under reduced pressure. Purification by flash chromatography on silica gel eluting with ammoniated chloroform/methanol (9: 1) gave the title compound as a yellow solid (125mg, 0.37)2mmol, 75%): electrospray MS (m/z, relative abundance) 336([ MH)]+，100)。
Example 10
5 ' -Phenylaminocarbonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Phenyl isocyanate (0.056ml, 0.515mmol) was added to 5' -aminospiro [ 1-azabicyclo [2.2.2] under nitrogen]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](119mg, 0.514mmol) in dry tetrahydrofuran (5ml) and stirred for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ammoniated chloroform/methanol (92.5: 7.5) to give the title compound as an off-white solid (155mg, 0.442mmol, 86%): electrospray MS (m/z, relative abundance) 351([ MH)]+，100)。
Example 11
5 ' -phenylsulfonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Benzenesulfonyl chloride (0.07ml, 0.55mmol) was added to 5' -aminospiro [ 1-azabicyclo [2.2.2] under nitrogen]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](115mg, 0.5mmol) in anhydrous pyridine (5ml) and stirred for 4 h. The solvent was evaporated under high vacuum, the residue partitioned between saturated aqueous sodium carbonate (2ml) and chloroform (10ml), the layers separated and the aqueous phase extracted with chloroform (2X 5 ml). The combined organic layers were dried (magnesium sulfate), the solvent was evaporated under reduced pressure, and the residue was re-evaporated from ethanol (3 × 10ml) under reduced pressure. The title compound was obtained as a yellow solid (179mg, 0.5mmol, 100%): electrospray MS (m/z, relative abundance) 372([ MH)]+，100)。
Example 12
5 ' - (N-methylamino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Sodium (50mg, 2.17mmol) was slowly added to (exothermic) methanol (1) under nitrogenml) and stirred for 1 hour. Adding 5' -aminospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](115mg, 0.5mmol) and paraformaldehyde (35mg, 1.17mmol) were stirred for 16 hours. The reaction was stirred at 50 ℃ for 4 h, sodium borohydride (53mg, 1.4mmol) was added and heated at reflux for 1 h. Then, 1N aqueous potassium hydroxide (0.4ml) was added and stirring was continued under reflux for 2 hours. The solvent was evaporated under reduced pressure, the residue partitioned between water (1ml) and chloroform (4ml), the layers were separated and the aqueous phase was extracted with chloroform (2X 4 ml). The combined organic layers were washed with brine (1ml), dried (magnesium sulfate), evaporated under reduced pressure and purified by flash chromatography on silica gel eluting with ammoniated chloroform/methanol (95: 5) to give the title compound as an off-white solid (78mg, 0.32mmol, 64%): electrospray MS (m/z, relative abundance) 246([ MH)]+，100)。
Example 13A
5 ' - (N, N-dimethylamino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Sodium cyanoborohydride (63mg, 1mmol) was dissolved in methanol (2.5ml), anhydrous zinc chloride (69mg, 0.5mmol) was added, stirring was carried out for 30 minutes, and the resulting solution was added to 5' -aminospiro [ 1-azabicyclo [2.2.2] 2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](115mg, 0.5mmol) and a solution of 37% aqueous formaldehyde (0.12ml, 1.6mmol) in methanol (2.5ml) were stirred for 20 hours. Poured into 1N aqueous potassium hydroxide (10ml), stirred for 1 hour, evaporated under reduced pressure and the residue aqueous solution extracted with chloroform (4X 10 ml). The combined extracts were dried (magnesium sulfate), evaporated under reduced pressure and purified by flash chromatography on silica gel eluting with ammoniated chloroform/methanol (97.5: 2.5) to give the title compound as an off-white solid (85mg, 0.33mmol, 66%): electrospray MS (m/z, relative abundance) 260([ MH)]+，100)。
Example 13B
(R) - (-) -5 ' - (N, N-dimethylamino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
According to the same phase as in example 13AThe same procedure was used for the treatment of the enantiomer (R) - (-) -5' -aminospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](231mg, 1mmol) to give the title compound (178mg, 0.69mmol, 69%): electrospray MS (m/z, relative abundance) 260([ MH)]+，100)。
Example 14A
(S) - (+) -5 ' - (E) - (phenylvinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
(S) - (+) -5' -bromospiro [ 1-azabicyclo [2.2.2] in thick-walled, threaded glass test tubes containing a magnetic stirrer]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](150mg, 0.51mmol), styrene (0.07ml, 0.61mmol), palladium (II) acetate (1.2mg, 0.0053mmol), tri-O-tolylphosphine (6.4mg, 0.021mmol) and triethylamine (0.5ml, 3.6mmol) in anhydrous acetonitrile (0.5ml) was purged with argon and sealed with a polytetrafluoroethylene stopper and FETFE O-ring. The mixture was stirred and heated at 100 ℃ for 2 h, cooled to room temperature, dissolved in chloroform (10ml), washed with saturated aqueous sodium carbonate (1ml), dried (magnesium sulphate) and evaporated under reduced pressure. Recrystallisation from ethyl acetate gave the title compound as a pale brown solid (90mg, 0.28mmol, 55%): electrospray MS (m/z, relative abundance) 319([ MH)]+，100)。
Example 14B
(R) - (-) -5 ' - (E) - (phenylvinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
The enantiomer (R) - (-) -5' -bromospiro [ 1-azabicyclo [2.2.2] was treated in the same manner as described in example 14A]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](295mg, 1mmol), purification by flash chromatography (eluting with ammoniated chloroform/methanol 98: 2 to 96: 4) to give the title compound (132mg, 0.41mmol, 41%): electrospray MS (m/z, relative abundance) 319([ MH)]+，100)。
Example 15A
(S) - (+) -5 ' - (4-morpholino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Sodium tert-butoxide (56.6mg, 0.59mmol), tris (dibenzylideneacetone) dipalladium (15.4mg, 0.017mmol) and 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (21mg, 0.034mmol) were mixed in a thick-walled glass tube containing a magnetic stirrer and argon was bubbled through. Adding (S) - (+) -5' -bromospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](130mg, 0.44mmol), morpholine (0.066ml, 0.76mmol) and anhydrous tetrahydrofuran (3ml) were sealed with a teflon plug and a FETFE O-ring, stirred and heated at 100 ℃ for 72 hours. The mixture was cooled to room temperature, dissolved in chloroform (25ml), washed with brine (3 × 2ml), dried (magnesium sulfate), evaporated under reduced pressure, purified by flash chromatography on silica gel (eluting with ammoniated ether/methanol 4: 1), and recrystallized from ethyl acetate to give the title compound as a brown solid (35mg, 0.12mmol, 26%): electrospray MS (m/z, relative abundance) 302([ MH)]+，100)。
Example 15B
(R) - (-) -5 ' - (4-morpholino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
The enantiomer (R) - (-) -5' -bromospiro [ 1-azabicyclo [2.2.2] was treated in the same manner as described in example 15A]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](580mg, 1.965mmol) to give the title compound (187mg, 0.62mmol, 32%): electrospray MS (m/z, relative abundance) 302([ MH)]+，100)。
Example 16
(R) - (-) -5 ' - (1-azetidinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
The (R) - (-) -5' -bromospiro [ 1-azabicyclo [2.2.2] is]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](295mg, 1mmol), azetidine (0.101ml, 1.5mmol), sodium tert-butoxide (135mg, 1.4mmol), tris (dibenzylideneacetone) dipalladium (46mg, 0.05mmol), 2' -bis (bisPhenylphosphino) -1, 1' -binaphthyl (62mg, 0.1mmol) and anhydrous tetrahydrofuran (9ml) were mixed in a thick-walled screw glass tube containing a magnetic stirrer, and argon gas was introduced and sealed with a teflon stopper and a FETFE O-ring. The mixture was stirred and heated at 75 ℃ for 4 h, cooled to room temperature, dissolved in chloroform (20ml), washed with brine (3 × 10ml), dried (magnesium sulfate), evaporated under reduced pressure and purified by flash chromatography on silica gel (eluting with ammoniated chloroform/methanol 95: 5) to give the title compound as a pale brown solid (230mg, 0.0.85mmol, 85%): chemically ionized MS (m/z, relative abundance) 272([ MH)]+，56)。
Example 17
(R) - (-) -5 ' - (2- (4-pyridyl) ethenyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
The (R) - (-) -5' -bromospiro [ 1-azabicyclo [2.2.2] is]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](295mg, 1mmol), 4-vinylpyridine (0.135ml, 1.25mmol), palladium (II) acetate (7.2mg, 0.032mmol), tri-O-tolylphosphine (38.7mg, 0.127mmol) and triethylamine (0.5ml, 3.6mmol) in dry acetonitrile (0.5ml) were mixed in a thick-walled, threaded glass tube containing a magnetic stirrer and purged with argon, sealed with a teflon stopper and a FETFE O-ring. The mixture was stirred and heated at 100 ℃ and 105 ℃ for 48 h, cooled to room temperature, dissolved in chloroform (25ml), washed with saturated aqueous sodium carbonate (2ml), dried (magnesium sulfate) and evaporated under reduced pressure. Purification by flash chromatography on silica gel (eluting with ammoniated chloroform/methanol 95: 5) followed by recrystallization from acetone gave the title compound (230mg, 0.72mmol, 72%): electrospray MS (m/z, relative abundance) 320([ MH)]+，100)。
Example 18
(R) - (-) -5 ' - (2- (2-pyridyl) ethenyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
(R) - (-) -5' -bromospiro [ 1-azabicyclo [ 1] -c[2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](150mg, 0.5 mmol). Purification by flash chromatography on silica gel (eluting with ammoniated ether/methanol 95: 5) followed by recrystallisation from acetonitrile gave the title compound (37mg, 0.12mmol, 23%): electrospray MS (m/z, relative abundance) 320([ MH)]+，100)。
Example 19
(R) - (-) -5 ' - (2-trimethylsilylethynyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
The (R) - (-) -5' -bromospiro [ 1-azabicyclo [2.2.2] is]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](295mg, 1mmol), trimethylsilylacetylene (0.355ml, 2.5mmol), tetrakis (triphenylphosphine) palladium (230mg, 0.2mmol), triethylamine (2ml) and dry acetonitrile (2ml) were mixed in a thick walled screw glass tube containing a magnetic stirrer and purged with argon and sealed with a teflon stopper and a FETFE O-ring. The mixture was stirred and heated at 100 ℃ for 4 h, cooled to room temperature, dissolved in chloroform (25ml), washed with saturated aqueous sodium carbonate (2ml), dried (magnesium sulphate) and evaporated under reduced pressure. Purification by flash chromatography on silica gel (eluting with ammoniated ether/methanol 9: 1) gave the title compound (280mg, 0.90mmol, 90%): chemical ionization MS (m/z, relative abundance) 313([ MH)]+，30)。
Example 20
(R) - (-) -5 ' -ethynylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
1M Tetrabutylammonium fluoride in tetrahydrofuran (1.3ml, 1.3mmol) was added to (R) - (-) -5' - (2-trimethylsilylethynyl) spiro [ 1-azabicyclo [2.2.2] under argon atmosphere at 0 deg.C]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](265mg, 0.85mmol) in dry tetrahydrofuran (5ml) was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (2ml), extracted with diethyl ether (5X 15ml), dried (magnesium sulfate), evaporated under reduced pressure and purified by flash chromatography on silica gel (eluting with ammoniated chloroform/methanol 95: 5) to give the titled compoundCompound (121mg, 0.50mmol, 59%): chemical ionization MS (m/z, relative abundance) 241([ MH)]+，19)。
Example 21
5 ' - (2-furyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Under reflux, the mixture containing 5' -bromospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A solution of (103.5mg, 0.351mmol), tris (dibenzylideneacetone) dipalladium (O) (14mg, 0.015mmol), tris (O-tolyl) phosphine (44.4mg, 0.146mmol), lithium chloride (62mg, 1.46mmol) and 2- (tri-n-butylstannyl) furan (0.17g, 0.476mmol) in 1, 2-dimethoxyethane (1ml) was heated for 2 hours. The solution was evaporated, the residue was dissolved in chloroform and filtered. The filtrate was evaporated and then purified by HPLC, eluting with a 0-25% 1: 2 gradient of 7M methanolic ammonia methanol chloroform to give the title compound as a pale solid (89mg, 0.313mmol, 89%): electrospray MS (m/z, relative abundance) 283([ MH)]+，100)。
Example 22
5 ' - (3-pyridinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Under reflux, the mixture containing 5' -bromospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A solution of (158mg, 0.535mmol), tris (dibenzylideneacetone) dipalladium (O) (23mg, 0.025mmol), tris (O-tolyl) phosphine (66mg, 0.217mmol), lithium chloride (99mg, 2.34mmol) and 3- (tri-n-butylstannyl) pyridine (0.3ml, about 0.3g, about 0.82mmol) in 1, 2-dimethoxyethane (2ml) was heated for 6 hours. The solution was evaporated, the residue was dissolved in chloroform and filtered. The filtrate was evaporated and then purified by HPLC, eluting with a 0-20% gradient of 7M methanolic ammonia methanol chloroform and chloroform 1: 2 to give the title compound as a pale solid (58mg, 0.198mmol, 37%): electrospray MS (m/z, relative abundance) 294([ MH)]+，80)，273(100)。
Example 23
5 ' -Methylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
On a bath maintained at 100 ℃, the solution containing 5' -bromospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A solution of (203mg, 0.687mmol), tris (dibenzylideneacetone) dipalladium (O) (33mg, 0.036mmol), tris (O-tolyl) phosphine (95mg, 0.312mmol), lithium chloride (241mg, 5.69mmol) and tetramethylstannane (1.0ml, 1.3g, 7.2mmol) in 2-methoxyethyl ether (5ml) was heated. After 3 hours, an additional portion of tetramethylstannane (1ml, 1.3g, 7.2mmol) was added and heating continued overnight. The solution was filtered, purified by HPLC, eluting with a 0-20% gradient of 7M methanolic ammonia methanol chloroform and chloroform 1: 2 to give the title compound as a pale solid (120mg, 0.519mmol, 76%): electrospray MS (m/z, relative abundance) 231([ MH)]+，100)。
Example 24
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] pyridine-5 'carbonitrile ] and spiro [ 1-azabicyclo [2.2.2] octane-3, 2' (3 'H) -furo [2, 3-b ] pyridine-5' carboxamide ]
On a bath maintained at 180 ℃, the solution containing 5' -bromospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A solution of (165mg, 0.558mmol) and copper (I) cyanide (600mg, 1.3g, ca. 7.2mmol) in 1-methyl-2-pyrrolidone (5ml) was heated overnight and then cooled. The solution was then partitioned between liquid ammonia and chloroform, the organic layer was separated, then dried (magnesium sulfate), filtered and evaporated. Purifying the residue by HPLC, and gradient eluting with 0-20% of 7M methanol to ammonia, methanol to chloroform and chloroform at a ratio of 1: 2 to obtain spiro [ 1-azabicyclo [2.2.2] as a pale solid]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine-5' carbonitriles](52mg, 0.216mmol, 39%): DCI MS (m/z, relative abundance) 242([ MH)]+100) and spiro [ 1-azabicyclo [2.2.2] as pale solid]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine-5' carboxamides](71mg, 0.274mmol, 49%): electrospray MS(m/z, relative abundance) 260([ MH)]+，100)。
Example 25
5 ' -Vinylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Under reflux, the mixture containing 5' -bromospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]A solution of (150mg, 0.508mmol), tris (dibenzylideneacetone) dipalladium (O) (22mg, 0.024mmol), tris (O-tolyl) phosphine (63mg, 0.206mmol), lithium chloride (103mg, 2.43mmol) and tri-n-butylvinylstannane (188mg, 0.592mmol) in 1, 2-dimethoxyethane (10ml) was heated overnight. The solution was evaporated, the residue dissolved in chloroform and filtered. The filtrate was evaporated and then purified by HPLC, eluting with a 0-25% 1: 2 gradient of 7M methanolic ammonia methanol chloroform to give the title compound as a pale solid (93mg, 0.385mmol, 76%): electrospray MS (m/z, relative abundance) 243([ MH)]+，100)。
Example 26
(R) - (-) -5 '-N' - (3-chlorophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] pyridine ]
Reacting (R) - (-) -5' -aminospiro [ 1-azabicyclo [2.2.2] under nitrogen atmosphere]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](65mg or 0.28mmol) was suspended in 2.7ml of anhydrous tetrahydrofuran. 3-chlorophenyl isocyanate (35. mu.l) was added and the suspension was stirred at room temperature for 5 hours. The tetrahydrofuran was removed in vacuo and the crude product was purified by flash chromatography. Elution with 20-40% methanol/chloroform (ammoniated with ammonium hydroxide) gave a spot product of the desired product. The solvent was removed in vacuo and the residue was dissolved in chloroform and dried (magnesium sulfate). Evaporation was repeated twice more with two portions of ether to give 100mg (92%) of a white solid. Electrospray MS 385 and 387[ MH ]]+。
Example 27
(R) - (-) -5 '-N' - (2-nitrophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] pyridine ]
The title compound was prepared in the same manner as described in example 27, but using 2-nitrophenyl isocyanate instead of 3-chlorophenyl isocyanate; yield 97mg (88%) of yellow powder. Electrospray MS 396[ MH ]]+。
Example 28
(R) - (-) -5 ' -N, N-diethylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Sodium cyanoborohydride (190mg or 3.0mmol) and zinc chloride (206mg or 1.5mmol) were added to 3.0ml of anhydrous methanol under a nitrogen atmosphere. Complete dissolution was achieved after 5 minutes of stirring. Adding (R) - (-) -5' -aminospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](230mg or 1.0mmol) followed by addition of acetaldehyde (0.335ml or 6.0 mmol). The suspension was stirred at room temperature for 16 hours. The methanol was concentrated in vacuo and the suspension was poured into 20ml of 1N sodium hydroxide. The aqueous layer was extracted four times with 20ml each time with chloroform, the extracts were combined and dried (magnesium sulfate) and evaporated in vacuo. The crude product was purified by flash chromatography eluting with 6/3/1/0.1 ethyl acetate/methanol/water (ammonified with ammonium hydroxide) followed by 3/6/1/0.1 ethyl acetate/methanol/water (ammonified with ammonium hydroxide). The solvent was removed in vacuo and the residue was dissolved in chloroform and dried (magnesium sulfate). 0.227g (79%) of a light brown syrup was obtained. Electrospray MS 288[ MH]+。
Example 29
(R) - (-) -5 ' -N-Ethylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Mixing (R) - (-) -5' -aminospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](230mg or 1.0mmol) and sodium cyanoborohydride are suspended in 6.2ml of anhydrous methanol. Acetaldehyde (90. mu.l or 1.1mmol) and the solution were stirred at room temperature for 16 hours. The methanol was removed in vacuo and the residue was dissolved in 2ml of water and 8ml of chloroform. Separating the layersAnd the aqueous layer was extracted three more times. The combined organic layers were dried (magnesium sulfate) and evaporated in vacuo. The crude product was purified by flash chromatography eluting with a 3-15% methanol/chloroform (ammoniated) gradient. The solvent was evaporated in vacuo and twice more with two portions of ether. The residue was suspended in ether and collected by filtration. After washing with diethyl ether and drying under high vacuum 81mg (31%) of a white powder are obtained. Electrospray MS 260[ MH]+。
Example 30
(R) - (-) -5 ' -N-benzylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Prepared according to the method of example 12. 247mg (77%) of a white powder are obtained from 1.0 mmol. Electrospray MS 322[ MH ]]+。
Example 31
(R) - (-) -5 ' -N-formylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
98% formic acid (2.1ml) and acetic anhydride (0.7ml) were mixed under nitrogen and cooled on an ice bath. Adding (R) - (-) -5' -aminospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](230mg or 1.0mmol) and the reaction was allowed to warm to room temperature. The reaction was stirred for 26 hours and then poured into saturated sodium carbonate with stirring. Solid sodium carbonate was added to pH to be alkaline again, and then the aqueous layer was extracted with four portions of chloroform. The extracts were combined, dried (magnesium sulfate) and evaporated in vacuo. The crude product was purified by flash chromatography eluting with a 2-10% ammoniated methanol/chloroform gradient. The solvent was removed in vacuo, the residue dissolved in chloroform, dried (magnesium sulfate) and evaporated in vacuo. The solvent was driven off twice more with two portions of ether to yield 0.2g (77%) of a white solid. Electrospray MS 260[ MH]+。
Example 32
(R) - (-) -5 ' -N-acetaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
In a nitrogen atmosphereThen, (R) - (-) -5' -aminospiro [ 1-azabicyclo [2.2.2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](230mg or 1.0mmol) was dissolved in 3ml of anhydrous pyridine. Acetic anhydride (0.1ml or 1.1mmol) was added and the solution was heated at 100 ℃ for 40 hours. Pyridine was removed in vacuo and the residue was dissolved in 8ml chloroform and washed with 4ml saturated sodium bicarbonate. The aqueous layer was extracted two more times with chloroform and the combined organic layers were dried (magnesium sulfate) and evaporated in vacuo. Purifying by flash chromatography, and eluting with 3-20% ammoniated methanol/chloroform gradient to obtain the desired product. The solvent was removed in vacuo and driven off twice with two portions of ether. 154mg (56%) of a white solid were obtained. Chemical ionization of MS 274[ MH ]]+。
Example 33
4 '-Chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2' (3 'H) -furo [2, 3-b ] pyridine ] and 4' -Chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [3, 2-c ] pyridine ]
A4 '-chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2' (3 'H) -furo [2, 3-b ] pyridine ] borane complex and a 2' -chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [3, 2-c ] pyridine ] borane complex were prepared from 2.36g (7.84mmol) of 3- (2, 4-dichloropyridin-3-ylmethyl) -3-hydroxy-1-azabicyclo [2.2.2] octane N-borane complex and 319mg (7.97mmol) of sodium hydride in dimethylformamide as described for preparation 2. Treatment of the mixture with aqueous hydrobromic acid in acetone followed by flash chromatography on neutral silica gel (eluting with a 98: 2 ammoniated chloroform/methanol mixture) gave 559mg of 4 '-chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2' (3 'H) -furo [2, 3-b ] pyridine ], m.p.109-110 deg.C (diethyl ether) and 463mg of 4' -chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [3, 2-c ] pyridine, m.p.113-115 deg.C.
Example 34
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2, 3-b ] pyridine ]
The 4' -chlorospiro [ 1-azabicyclo [2.2.2] from example 33]Octane-3, 2 '(3' H) -furoPyrano [2, 3-b ]]Pyridine compound](125mg or 5.0mmol) was dissolved in 50ml of anhydrous methanol, and 25mg of 10% palladium on charcoal was added. The reaction flask was placed in a Parr apparatus under a hydrogen atmosphere and shaken for 2.5 hours. Pd/C was removed by filtration and washed with methanol. The solvent was removed in vacuo and the residue was dissolved in chloroform and methanol and transferred to a vial. The solvent was removed in vacuo and driven off again with two portions of ether. After drying under high vacuum, 112mg of an off-white powder (104% with residual solvent) are obtained. Electrospray MS 217[ MH ]]+。
Example 35
4 ' -Methoxysilospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Sodium hydride (241mg, 6.0mmol) was added to 76mg (0.30mmol) of 4' -chlorospiro [ 1-azabicyclo [2.2.2] under nitrogen]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]To 25ml of ice-cold methanol solution. The resulting solution was heated to reflux and stirred for 4 days, then cooled to room temperature, poured into 30ml of water and extracted with chloroform (3 × 30 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, concentrated in vacuo, and subjected to flash chromatography on neutral silica gel, eluting with a 9: 1 mixture of ammoniated chloroform/methanol, to give the title compound as a white solid, 50mg (67%): electrospray MS (m/z, relative abundance) 247([ MH)]+)。
Example 36
4 ' -Thienylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Sodium hydride (151mg, 3.77mmol) was added to 97mg (0.387mmol) of 4' -chlorospiro [ 1-azabicyclo [2.2.2] under nitrogen]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]0.40ml (3.91mmol) of thiophenol and 0.10ml of methanol in 15ml of dioxane. The reaction was refluxed for 4 days, then cooled to room temperature, diluted with 30ml of water and extracted with chloroform (3X 30 ml). Drying the combined organic extracts over anhydrous magnesium sulfate, concentrating under vacuum, subjecting the residue to neutral silica gel flash chromatography, eluting with 98: 2 ammoniated chloroform/methanol mixture to give a colorless oilTitle compound 65mg (52%): electrospray MS (m/z, relative abundance) 325([ MH)]+)。
Example 37
4 ' - (N-2-aminoethyl) aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
74mg (0.295mmol) of 4' -chlorospiro [ 1-azabicyclo [2.2.2] under nitrogen]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]Heated to reflux and stirred for 4 days. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in 20ml of saturated aqueous sodium carbonate solution and extracted with chloroform (3X 25 ml). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a dark oil 80mg (100%): electrospray MS (m/z, relative abundance) 275([ MH)]+)。
Example 38
4 ' - (4-N-methylpiperazin-1-yl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Under a nitrogen atmosphere, 97mg (0.387mmol) of 4' -chlorospiro [ 1-azabicyclo [2.2.2] 2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]1ml of 1-methylpiperazine solution is heated to reflux and stirred for 18 hours. After cooling to room temperature, it was diluted with 40ml of water, basified with 2ml of saturated aqueous sodium carbonate solution and extracted with chloroform (3X 25 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash chromatographed on neutral silica gel, eluting with a 4: 1 ammoniated chloroform/methanol mixture to give the title compound as an amber oil 59mg (48%): electrospray MS (m/z, relative abundance) 315([ MH)]+)。
Example 39
4 ' - (phenylmethyl) aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Under a nitrogen atmosphere, 97mg (0.387mmol) of 4' -chlorospiro [ 1-azabicyclo [2.2.2] 2]Octane-3, 2 '(3' H)-furo [2, 3-b ] s]Pyridine compound]Is heated to reflux and stirred for 18 hours. After cooling to room temperature, it was diluted with 40ml of water, basified with 2ml of saturated aqueous sodium carbonate solution and extracted with chloroform (3X 25 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash chromatographed on neutral silica gel, eluting with a 9: 1 ammoniated chloroform/methanol mixture to give the title compound as a white solid, 42mg (34%): electrospray MS (m/z, relative abundance) 322([ MH)]+)。
Example 40
4 ' - (methylamino) aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
In a steel reactor 151mg (0.60mmol) of 4' -chlorospiro [ 1-azabicyclo [2.2.2] 2]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]The solution in 25ml of 40% aqueous methylamine solution was heated to 175 ℃ for 18 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 10ml of ethanol containing 0.4ml of concentrated hydrochloric acid, and the solution was left overnight. After filtration, the solution was concentrated in vacuo and the residue was crystallized from isopropanol to give 147mg of the title compound as a white solid: electrospray MS (m/z, relative abundance) 246([ MH)]+)。
EXAMPLE 41
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine-7 ' -oxide ]
Under reflux spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound](2.88g, 13.3mmol) and aqueous hydrogen peroxide (30%, 5ml) in acetic acid (20ml) were heated. After 16 hours and 24 hours, respectively, hydrogen peroxide was added and heating was continued for a total of 48 hours. The solution was then evaporated and the residue was subsequently redissolved in ethanol (40ml) saturated with sulphur dioxide. After 4 h, the solution was evaporated and the residue was purified by HPLC on silica gel, gradient eluted with a mixture of 0-50% solvent (7M methanolic ammonia (25%) methanol (25%) chloroform (50%)) and chloroform. The title compound (934mg, 4.0mmol, 30%) was a solid:DCI MS 233([MH]+)。
example 42
Spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine-6 ' -carbonitrile ]
Spiro [ 1-azabicyclo [2.2.2] s]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine-7' -oxide](95mg, 0.41mmol) was dissolved in acetonitrile (2 ml). Triethylamine (0.12ml, 87mg, 0.86mmol) and trimethylsilylcyanide (0.2ml, 149mg, 1.5mmol) were added successively. The solution was stirred at room temperature overnight and then heated to reflux temperature. After about 8 hours, more trimethylsilyl cyanide (0.2ml) was added. After heating at reflux overnight, the solution was cooled. Excess methanol was added and the solution was left at room temperature for 4 hours and subsequently evaporated. The residue was purified by HPLC on silica gel, eluting with a gradient of 0-25% solvent (7M methanolic ammonia (25%) methanol (25%) chloroform (50%)) and chloroform mixture. The title compound (50mg, 0.21mmol, 51%) was a solid: electrospray MS 242([ MH)]+)。
Example 43
6 ' -Chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Under reflux spiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine-7' -oxide]A solution of (98mg, 0.42mmol) of phosphorus oxychloride (2ml) was heated for 2 hours. The solution was evaporated and the residue partitioned between aqueous potassium carbonate and chloroform, then the organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified by HPLC on silica gel, eluting with a gradient of 0-25% solvent (7M methanolic ammonia (25%) methanol (25%) chloroform (50%)) and chloroform mixture. The title compound (26mg, 0.10mmol, 25%) was a solid: electrospray MS 251([ MH)]+Is composed of35Cl) and 253([ MH)]+Is composed of37Cl)。
Example 44
6 ' -Fluorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
(a)6 ' -Fluorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ] N-borane complexes
Phenyllithium (1.8M in cyclohexane, 13.5ml) was added to THF (15ml) under argon. Diisopropylamine (0.5ml) was added and the solution was cooled to-78 ℃ (temperature of dry ice/acetone bath). To the resulting solution was added dropwise 2, 6-difluoropyridine (1.23ml, 1.56g, 13.6mmol), followed by addition of spiro [ 1-azabicyclo [2.2.2] after 1 hour]Octane-3, 2' -oxiranes]N-borane complex (765mg, 5.0mmol) in tetrahydrofuran. The solution was stirred at-78 ℃ for 1 hour, then the cooling bath was replaced by a dry ice/acetonitrile bath. The solution was then stirred overnight, warmed to room temperature. Saturated aqueous sodium bicarbonate was added, followed by extraction of the solution with chloroform. The extract was then dried (magnesium sulfate), filtered and evaporated. The residue was dissolved in DMF (20ml) and added to a suspension of hexane washed sodium hydride (60% mixture of mineral oils, 507mg, 12.7mmol) in DMF (20ml) and stirred at 0 ℃. The solution was stirred overnight and allowed to warm to room temperature. To the solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The extracts were dried (magnesium sulfate), filtered and evaporated, and the residue was purified by HPLC, eluting with a gradient of 5-50% ethyl acetate and hexane to give the sub-title compound (102mg, 8%, 0.41 mmol): electrospray MS (M/z)247[ M-H]+。
(b)6 ' -Fluorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]
Reacting 6' -fluorospiro [ 1-azabicyclo [2.2.2]]Octane-3, 2 '(3' H) -furo [2, 3-b]Pyridine compound]The N-borane complex (98mg, 0.40mmol) was dissolved in acetone (5 ml). 48% aqueous hydrobromic acid (2ml) was diluted with water (2ml) and added to the above solution. The resulting mixture was stirred at room temperature overnight. The solution was then evaporated and partitioned between aqueous sodium carbonate and chloroform. The organic extracts were dried (magnesium sulfate), filtered and evaporated, and the residue was purified by HPLC using 0-25% 7M methanol 1: 2 to make ammonia, methanol, chloroform and chloroformElution was repeated to give the title compound as a solid (39mg, 0.168mmol, 43%): electrospray MS (m/z, relative abundance) 235([ MH)]+，100)。

Claims (16)

1. A compound of formula I or enantiomers and pharmaceutically acceptable salts thereof:wherein n is 0; m is 1; p is 0; x is oxygen; y is CH, N or NO; w is oxygen, H2Or F2(ii) a A is C (R)2) (ii) a G is C (R)3) (ii) a D is C (R)4)；R2、R3And R4Independently of each other hydrogen, halogen atoms, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3Or R is2And R3Or R3And R4May combine to form another six-membered aromatic or heteroaromatic ring containing 0-2 nitrogen atoms, sharing a and G or G and D, respectively, and may be independently substituted with 1-2 of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3，R5And R6Independently of each other is hydrogen, C1-C4Alkyl, C (O) R7、C(O)NHR8、C(O)OR9、SO2R10Or may together be (CH)2)jQ(CH2)kWherein Q is O, S, NR11Or a bond; j is 2 to 7; k is 0 to 2; r7、R8、R9、R10And R11Independently is C1-C4Alkyl, aryl or heteroaryl, wherein aryl means a phenyl ring optionally substituted with one to three of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3(ii) a Heteroaryl refers to a 5 or 6 membered aromatic ring containing one or two nitrogen atoms, the carbon atoms on the ring being optionally substituted with one to three of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3；R5And R6May together be (CH)2)jQ(CH2)kWherein Q is O, S, NR11Or a bond, j is 2-7 and k is 0-2, such that a 3-7 membered ring is formed.
2. The compound of claim 1, which is the following compound or an enantiomer or a pharmaceutically acceptable salt thereof: 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 ' - (phenylamino carbonylamino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (benzenesulfonylamino) 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-formylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' -N-acetamido-spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] isoquinoline ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] quinoline ]; 5 ' -vinylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (E) - (styryl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' h) -furo [2, 3-b ] pyridine ]; 5 ' - (4-morpholino) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (1-azetidinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (E) - (2- (4-pyridyl) vinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (E) - (2- (2-pyridyl) vinyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (2-trimethylsilylethynyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' -ethynylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (2-furyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' - (3-pyridyl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 5 ' -methyl spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine-5 ' carbonitrile ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine-5 ' carboxamide ]; 5 '-N' - (3-chlorophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] pyridine ]; 5 '-N' - (2-nitrophenyl) aminocarbonylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b ] pyridine ]; 4 ' -chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -methoxyspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -thiophenylspiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' - (N-2-aminoethyl) aminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -benzylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' -methylaminospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; 4 ' - (4-N-methylpiperazin-1-yl) spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' - (3 ' H) -furo [2, 3-b ] pyridine ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [3, 2-c ] pyridine ]; 6 ' -fluorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ]; spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine-6 ' -carbonitrile ]; 6 ' -Chlorospiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine ].
3. The compound of claim 1, wherein Y is NO.
4. The compound of claim 3 which is spiro [ 1-azabicyclo [2.2.2] octane-3, 2 ' (3 ' H) -furo [2, 3-b ] pyridine-7 ' -oxide ] or a pharmaceutically acceptable salt or enantiomer thereof.
5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable inert diluent or carrier.
6. The use of a compound as defined in any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prophylaxis of human diseases or disorders in which activation of the α 7 nicotinic receptor is beneficial.
7. The use according to claim 6, wherein the human disease or disorder is a psychotic disorder or an intellectual impairment disorder.
8. The use of claim 7, wherein the disorder or disease is alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, attention deficit hyperactivity disorder.
9. The use according to claim 7, wherein the disorder is anxiety, schizophrenia or mania or manic depression.
10. The use according to claim 7, wherein the disease is Parkinson's disease, Huntington's disease, Tourette's syndrome, or a neurodegenerative disease in which there is loss of cholinergic synapses.
11. The use of claim 6, wherein the human disease or disorder is jet lag, smoking cessation, nicotine addiction including exposure to products containing nicotine, pain, and ulcerative colitis.
12. A process for the preparation of a compound of formula I as defined in claim 1 wherein Y is N, or an enantiomer or a pharmaceutically acceptable salt thereof, which process comprises: removal of borane complexes from compounds of formula II by heating with acids or in alcoholic solvents in suitable solventsWhen W is equal to F2If desired or necessary, by converting the resulting compound of the formula I or an enantiomer or an acid addition salt thereof into a pharmaceutically acceptable acid addition salt or by converting the resulting racemic mixture of the compound of the formula I into its enantiomer.
13. The method according to claim 12, wherein R2To hydroxyl groups by rearrangement of a compound of formula I as defined in claim 1 wherein Y is NO by treatment with a carboxylic acid anhydride in a suitable solvent.
14. The method according to claim 12, wherein R2For chloro-substitution, the process comprises rearranging a compound of formula I as defined in claim 1, wherein Y is NO, by treatment with a chlorine source in a suitable solvent.
15. The method according to claim 12, wherein R2Is cyano, by rearrangement of a compound of formula I as defined in claim 1, wherein Y is NO, by treatment with a cyanide source in a suitable solvent.
16. A compound of the formulaOr an enantiomer thereof:wherein n is 0; m is 1; p is 0; x is oxygen; w is oxygen, H2Or F2(ii) a A is C (R)2) (ii) a G is C (R)3) (ii) a D is C (R)4)；R2、R3And R4Independently of each other hydrogen, halogen atoms, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3Or R is2And R3Or R3And R4May combine to form another six-membered aromatic or heteroaromatic ring containing 0-2 nitrogen atoms, sharing a and G or G and D, respectively, and may be independently substituted with 1-2 of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, aryl, heteroaryl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3、-OSO2CF3；R5And R6Independently of each other is hydrogen, C1-C4Alkyl, C (O) R7、C(O)NHR8、C(O)OR9、SO2R10Or may together be (CH)2)jQ(CH2)kWherein Q is O, S, NR11Or a bond; j is 2 to 7; k is 0 to 2;
R7、R8、R9、R10and R11Independently is C1-C4An alkyl, aryl or heteroaryl group, wherein the aryl group is a phenyl ring optionally substituted with one to three of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3；
Heteroaryl refers to a 5 or 6 membered aromatic ring containing one or two nitrogen atoms, the carbon atoms on the ring being optionally substituted with one to three of the following substituents: hydrogen, halogen atom, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, OH, OC1-C4Alkyl, CO2R1、-CN、-NO2、-NR5R6、-CF3；R5And R6May together be (CH)2)jQ(CH2)kWherein Q is O, S, NR11Or a bond, j is 2-7 and k is 0-2, such that a 3-7 membered ring is formed.
HK01102261.7A 1997-07-18 1998-07-10 Spiroazabicyclic heterocyclic compounds, a method for producing the same and use thereof HK1031382B (en)

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SE9702746A SE9702746D0 (en) 1997-07-18 1997-07-18 New compounds
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SE9800977-2 1998-03-24
SE9800977A SE9800977D0 (en) 1998-03-24 1998-03-24 New compounds
PCT/SE1998/001364 WO1999003859A1 (en) 1997-07-18 1998-07-10 Novel spiroazabicyclic heterocyclic compounds

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