UA61964C2 - New spiroazabicyclic heterocyclic compounds - Google Patents

Abstract

A compound of formula (I) wherein n is 0 or 1; m is 0 or 1; p is 0 or 1; X is oxygen or sulfur, Y is CH, N or NO; W is oxygen, H2 or F2; A is N or C(R2); G is N or C(R3); D is N or C(R4); with the proviso that no more than i one of A, G, and D is nitrogen, but at least one of Y, A, G, and D is nitrogen or NO; R1 is hydrogen or C1 to C4 alkyl; R2, R3, and R4 are independently hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, heteroaryl, OH, OC1-C4 alkyl, CO2R1, -CN, -NO2, -NR5R6, -CF3, -OSO2CF3 or R2 and R3, or R3 and R4, respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero andtwo nitrogen atoms, and substituted with one to two of the following substituents: independently hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, heteroaryl, OH, OC1-C4 alkyl, CO2R1, -CN, -NO2, -NR5R6, -CF3, -OSO2CF3; R5 and R6 independently hydrogen, C1-C4 alkyl, C(O)R7, C(O)NHR8, C(O)OR9, SO2R10 or may together be (CH2)jQ(CH2)k where Q is O, S, NR11, or a bond; j is 2 to 7, k is 0 to 2; R7, R8, R9, R10, and R11 are independently C1-C4 alkyl, aryl, or heteroaryl, or an enantiomer thereof, and the pharmaceutically acceptable salts thereof, processes for preparing them, composition containing them, and their use in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders. I

Description

Description of the invention

The invention relates to new spiroazabicyclic heterocyclic amines or their pharmaceutically acceptable 2 salts, methods of their preparation, pharmaceutical compositions containing them, and their use in therapy.

The next goal is to provide active compounds that are potent ligands for nicotinic acetylcholine receptors (PASAK 5).

The use of compounds that bind nicotinic acetylcholine receptors in the treatment of a number of diseases involving reduced cholinergic function, such as Alzheimer's disease, cognitive or attentional impairment, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia, Tourette's disease and Parkinson's, was discussed in the work of MesOopai ei ai. (1995).

Moiiesciag Viiodu, Spetivigu apia Rnaptasiodu, SParieg 5, Appia! Kerogov ip Meaisipai Spetivigu, my.30, yr.41-50, Asadetis Rgevzv Ips., Zap Oiedo, SA; and MUShiatve ei aiYi. (1994), "Meygopa! Misoiipis AsefuiIspoiipe

Keseriog", Ogid Memuz apa Regzresiimev, moi.7, pp.205-223. 12 US patent 5468875 describes 1-azabicyclo|2.2.1|-hept-Z-yl esters of M-alkylcarbamic acids, which are active muscarinic agents of central of the nervous system, which can be used in the treatment of Alzheimer's disease and other diseases. 1-Azabicyclo|2.2.2|octan-Z-yl esters of M-(2-alkoxyphenyl)carbamic acids are described in RNagta?ie, my.48, 465-466 (1933), as well as their local anesthetic activity.1-Azabicyclo|2.2.1|-octan-3-yl ethers

M-phenylcarbamic acids substituted in the ortho-position of the phenyl ring are described as local anesthetics in Asia Ripagt. Zpcesis, 7, 239-246 (1970).

Furopyridines, which can be used to regulate synaptic transmission, are described in MO 97/05139.

In accordance with the invention, it was found that the compound of the formula | sch mi o (SNo)t bu.

M risn;) | 70 " actions of Uh Fo (Sup - de

So n is equal to 0 or 1, y-oi t is equal to 0 or 1, p is equal to 0 or 1,

M represents CH, M or MO, and X represents oxygen or sulfur, -o

M represents oxygen, H» or P», c A represents M or C(B2), :z» C represents M or se,

O represents M or C(B7), provided that no more than one of A, b, and OO represents nitrogen, but at least one of U, A, b, and Y

He") represents nitrogen or MO, - in! represents hydrogen or C1-C1-alkyl, 2, B3 and b7 represent, independently, hydrogen, halogen, C4-C6-alkyl, C0-C1-alkenyl, C0-C1-alkynyl, aryl, and heteroaryl, OH, OS.-Su-alkyl, CO», -SM, -MO», -MA?EZU, -SEz, -0О80оСеz or VK? and KZ or VZ and VU, b 20, respectively, can together, with the participation of A and C or C and 0, respectively, form another six-membered aromatic or heteroaromatic ring that contains from zero to two nitrogen atoms and is substituted, independently, by one or by two of the following substituents: hydrogen, halogen, C4-C alkyl, Co-C alkenyl, Co-C alkynyl, aryl, heteroaryl, OH, OC-Cu alkyl, CO, -CM, -MO», -ME?E5, -SEz, -О5О»СЕ», 2? and 5, independently, represent hydrogen, C-C/-alkyl, CO)", C(OMNEZ, C(OOVU, 802879) or can also represent 11' together (CHO)IS(CH")K, where O represents O, 5, MK or communication,

GF) | is equal to 2-7, g K is equal to 0-2, 2", 8 in, vo and VC"! represent, independently, C 1-Cu alkyl, aryl or heteroaryl, or an enantiomer thereof and 60 its pharmaceutically acceptable salt is a strong ligand for nicotinic acetylcholine receptors.

Unless otherwise specified, C1-C1-alkyl groups specified herein, for example methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, may be straight or branched chain, i

C3-Cu;-alkyl groups can also be cyclic, for example, cyclopropyl, cyclobutyl.

Unless otherwise specified, C1-C6 alkyl groups referred to herein are, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, t-butyl, n-pentyl, isopentyl , tert-pentyl, neopentyl, n-hexyl or isohexyl, can be straight or branched, and C3-C6-alkyl groups can also be cyclic, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Unless otherwise specified, C1-C6-alkyl groups indicated herein, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, may be straight or branched.

Unless otherwise stated, C1-C1-alkenyl groups specified herein may contain one or two double bonds, for example, ethenyl, isopropenyl, n-butenyl, isobutenyl, allyl, 1,3-butadienyl.

Unless otherwise specified, C1-C1-alkynyl groups specified herein contain one triple bond, for example, ethynyl, propynyl, 1- or 2-butynyl. 70 The halogen specified here can be fluorine, chlorine, bromine or iodine.

Unless otherwise stated, aryl refers to a phenyl ring optionally substituted with one to three of the following substituents: hydrogen, halogen, C.4-C.alkyl, C.sub.1-C.sub.alkenyl, C.sub.2-C.sub.alkynyl, OH, OH .-C,-alkyl, Co, -SM, -MO», -ME?E5, -SEz.

Unless otherwise stated, heteroaryl refers to a five- or six-membered aromatic ring containing 75 one or two nitrogen atoms, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, or pyrazolyl, wherein the ring carbon atoms are optionally substituted with the following substituents from one to three: hydrogen, halogen, C1-Su-alkyl, Co-Su-alkenyl, Co-Su-alkynyl, OH, OS.-Su-alkyl, CO»B, -CM, -MO", - MA?V, -SEz,

IN? and 29 can together be (СНо)О(СНо)ю, where СО) represents О, 5, ME! whether connection and where | is 2-7, preferably 2-3, and K is a number from 0 to 2, so as to form a 3-7-membered ring, preferably a 5- or b-membered ring, for example, pyrrolidinyl, imidazolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl.

IN? and KZ can together, with the participation of A and C, form another six-membered aromatic or heteroaromatic ring, which contains from one to two nitrogen atoms and belongs to such groups as quinoline, 1,5-, 1,6-, 1,7- or 1,8-diazanaphthalene.

VZ and KE" can together, with the participation of A and 0, form another six-membered aromatic or heteroaromatic ch 29 ring, which contains from zero to two nitrogen atoms and belongs to such groups as isoquinoline, 2,5-, 2,6-, Ge) 2,1- or 2,8-diazanaphthalene.

The best compounds of the invention are compounds of formula I, where t is 1, n is 0, P is 0, X represents oxygen, MU represents Ho, A represents C(K2), O represents C(KU), O represents C(B7) . "

The best compounds of the invention include the following compounds: - spiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridines, |se) - 5-bromospiro| 1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridines, Fo - B5-phenylspiro|1-azabicyclo|2.2.2)octane-3,2 '-(3'H)-furoi|2,3-B|pyridines, - 5-nitrospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furoi|2,3- B|pyridines, "-- - 1-chlorospiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-BIisoquinolines, "so - 5-(phenylcarboxamido) spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridine, - 5-(phenylaminocarbonylamino)spiro|1-azabicyclo|2.2.2)octane-3 ,2'-(3'H)-furo|2,3-B|pyridines, - 5-(phenylsulfonylamido)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo |2,3-in|pyridine, - 5-aminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-in|pyridine, « 20 - 5- M-methylaminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-v|pyridine, s-v - 5-M,M-dimethylaminospiro|1-azabicyclo |2.2,2|octane-3,2'-(3'H)-furo/|2,3-vI|pyridines, c - 5-M,M-diethylaminospiro|1-azabicyclo|2.2.2|octane-3 ,2'-(3'H)- furo|2,3-Vpyridines, :z» - 5-M-ethylaminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-v|pyridines, - 5-M-benzylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-BIpyridine, - 5-M-formamidospiro|1-azabicyclo|2.2.2) octane-3,2'-(3'H)-furo|2,3-B|pyridines, b - 5-M-acetamidospiro|1-azabicyclo|2.2.2|octane-3.2'-(3'H)- furo|2.3-β|pyridines, - spiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-β|isoquinolines, - - spiro|1-azabicyclo |2.2.2)octane-3,2'-(3'H)-furo|2,3-B)quinolines, o - 5-ethenylspiro|1-azabicyclo|2.2.2|octane-3,2'-( 3'H)-furo|2,3-vI|pyridines, - 5-(E)-(phenylethenyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo| 2,3-β|pyridines, b» - 5-(4-morpholino)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines,

T» - 5-(1-azetidinyl)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridine, - 5-(E)- (2-(4-pyridyl)ethenyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo/|2,3-in|pyridine, - 5-(E) -(2-(2-pyridyl)ethenyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo/|2,3-in|pyridine, - 5-(2 -trimethylsilylethynyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-in|pyridine, - 5-ethynylspiro|1-azabicyclo|2.2.2|octane -3,2-(3'H)furo|2.3-B|pyridine, (F) - 5-(2-furyl)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)- furo|2,3-VIpyridines,

GI - 5-(3-pyridyl)spiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines, - 5-methylespiro|1-azabicyclo| 2.2.2) octane-3,2'-(3'H)-furo|2,3-B|pyridines, in - spiro|1-azabicyclo(|2.2.2)octane-3,2'-(3' H)-furoi|2,3-B|Ipyridine-5'-carbonitrile, - spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furoi|2,3-B| pyridine-5'-carboxamides, 5-M'-(3Z-chlorophenyl)aminocarbonylaminospiro|1-azabicyclo|2.2.2)octane-3,2-(3'H)-furo|2,3-B|pyridines, - 5-M-(2-nitrophenyl)aminocarbonylaminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridine, - 4-chlorospiro|1-azabicyclo|2.2 .2octane-3,2!-(3'H)-furo|2,3-BIpyridines, 65 - 4-methoxyspiro|1-azabicyclo(2.2.2|octane-3,2'-(3'H)-furoes |2,3-vIpyridines, - 4-phenylthiospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-v|pyridines,

- 4-(M-2-aminoethyl)aminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines, - 4-phenylaminospiro|1-azabicyclo| 2.2.2) octane-3,2'-(3'H)-furo|2,3-VIpyridines, - 4-methylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H) -furo|2,3-VIpyridines, - 4-(4-M-methylpiperazin-1-yl)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2, 3-B|pyridines, - 4-chlorospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-c|Ipyridines, - spiro|1-azabicyclo|2.2 .2|octane-3,2'-(3'H)-furo|2,3-c|pyridines, - spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)- furoi|2,3-B|pyridine-7"-oxides, - spiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furoi|2,3-VIpyridine-6' -carbonitrile, 70 - 6-chlorospiro|1-azabicyclo(2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines, - 6b'-(rtorspiro|1-azabicyclo|2.2 .2) octane-3,2'-(3'H)-furo|2,3-B|pyridine|, and their enantiomers and pharmaceutically acceptable salts.

Particularly preferred compounds of the invention are compounds of the formula I, where t is 1, n is 0, p is 0, X is oxygen, MU is HO, A- CH 0 is CH, and - SVU, which include the following compounds: - spiro|1 -azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridines, - spiro|1-azabicyclo|2.2.2)octane-3,2'-( 3'H)-furoi|2,3-B|pyridine-7"-oxide, - 5-bromospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furoi|2, 3-B|pyridines, - B5-phenylspiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridines, - 5-nitrospiro|1-azabicyclo |2.2.2) octane-3,2'-(3'H)-furo|2,3-B|pyridines, - 5-(phenylcarboxamido)spiro|1-azabicyclo|2.2.2|octane-3,2' -(3'H)-furoi|2,3-VIpyridines, - 5-(phenylaminocarbonylamino)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furoi|2,3- In|pyridines, - 5-(phenylsulfonylamido)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-in|pyridines, - 5-aminospiro|1- azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-in|pyridine, - 5-M-methylaminospiro|1-azabicyclo|2.2.2|octane-3,2' -(3'H)-furo|2,3-in|pyridine, Ha - 5-M,M-dimethylaminospiro|1-azabicy chloro|2.2.2|octane-3,2'-(3'H)-furo/|2,3-vI|pyridines, - 5-M,M-diethylaminospiro|1-azabicyclo|2.2.2|octane-3 . 2,3-in|pyridine, - 5-M-benzylaminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-in|pyridine, - 5-M -formamidospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridines, "I - 5-M-acetamidospiro|1-azabicyclo|2.2.2 |octane-3,2'-(3'H)-furo|2,3-in|pyridine, - 5-ethenylspiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)- furo|2,3-vI|pyridines, o - 5-(E)-(phenylethenyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3- in|pyridine, Ge»! - 5-(4-morpholino)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine, - 5-(1-azetidinyl)spiro|1 -azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridines, -- - 5-(E)-(2-(4-pyridyl)ethenyl)spiro |1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo/|2,3-in|pyridine, He) - 5-(E)-(2-(2-pyridyl) ethenyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo/|2,3-in|pyridine, - 5-(2-trimethylsilylethynyl)spiro|1-azabicyclo| 2.2.2|octane-3,2'-(3'H)-furo|2,3-in|pyridine, - 5-ethynylspiro|1-azabicyclo|2.2.2)octane-32'-(3'H) furoi|2.3-VIpyridines, « - 5-(2-furyl)spiro|1-azabicyclo(|2.2.2|octane-3,2'-(3'H)-furoi|2,3-VIpyridines, - 5- (3-pyridyl)spiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines, - c - 5-methylespiro|1-azabicyclo|2.2. 2) octane-3,2'-(3'H)-furo|2,3-B|pyridines, c - spiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H) -furoi|2,3-B|Ipyridine-5'-carbonitrile, "» - spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furoi|2,3-B| pyridine-5'-carboxamides, - 5-M-(3-chlorophenyl)aminocarbonylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3' H)-furo|2,3-VIpyridines, -5-M-(2-nitrophenyl)aminocarbonylaminospiro|1-azabicyclo|2.2.2|octane-3,27-(3'H)-furo/|2,3- Bipyridines.

Ge) In the reaction schemes and the text that follows, A, b, O, X, MU, M, 7, t, p and r, if not indicated separately, are - as defined above for formula I. (A ) Compounds where P is 0 and M represents M (Ce) Compounds of formula I, where p is 0 and X represents M, can be obtained by the methods depicted in scheme I. b 50 s"

F) name) 60 b5

Scheme I (р - 0) (СНо)т

M VK

5 -kh | and t (СНа)p I y

E

E! (СНо)t (СН)t

Si be vn Me m zm 5 t shk

And M (5) (СН;)n (СНо)н M

M IM

" "so (22) "- z5 (СН)t 0-8, as -0 ВН," and "

VN. And tt

M ХХ ХН 2

M y s (СН.)н г» х T (СНо)н

Her and

F A o y /g vu M Zh M s" (SN.)p

AND

Ф) име) Compounds of the formula I, where МУ - H»e and p is equal to 0, can be obtained by removing the protective group from compounds of the formula PA using an acid in a suitable solvent. Suitable acids include mineral, 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 best solvent is acetone. The reaction is usually carried out at a temperature of from about -107C to about 1002C, preferably from about 0"C to about 60"C. Alternatively, deprotection can be accomplished by heating the borane complex in alcohol solvents. The best way is to boil a solution of the complex in ethanol under reflux.

Compounds of formula I, where MU is O (oxygen) and P is 0, can be obtained by oxidation of compounds of formula PA, for example, using selenium dioxide or reaction first with M-bromosuccinimide, then with sodium bicarbonate and methyl sulfoxide followed by removal of the borane group, as described above.

Compounds of formula I, where MU is Po and p is 0, can be obtained from compounds of formula I, where M is 0, by reaction with a fluorinating agent, for example, diethylaminosulfur trifluoride.

Compounds of the formula HA can be obtained by cyclization of a compound of the formula I, where I represents fluorine, chlorine, bromine, iodine, -ОСН», -ЗРАЙ, -ЗСН3, -«502РЙ or -505СН»3, in the presence of a base in an inert solvent. Suitable bases include sodium hydride, sodium amide, potassium hydride, potassium tert-amylate, potassium tert-butoxide and potassium 70 bis(trimethylsilyl)amide. The best base is sodium hydride. Suitable inert solvents include

M,M-dimethylformamide, M-methylpyrrolidin-2-one, ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane, and dimethylsulfoxide. The best inert solvent is M,M-dimethylformamide. The reaction is usually carried out at a temperature of from about 107°C to about 100°C, preferably from about 207°C to about 66°C.

Compounds of the formula I, where Y represents fluorine, chlorine, bromine, iodine, -OSN z, -5RY, -"5SNZ, -502P PY or -5BO"CH", can be obtained by the reaction of a compound of the formula IM with a compound of the formula Y, where I .as defined above in an inert solvent. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1,4-dioxane. The best inert solvent is tetrahydrofuran. The reaction is usually carried out at a temperature of from about -100°C to about 0°C, preferably from about -78°C to about -2576°C.

Compounds of formula Y, wherein I is as defined above, may be prepared from compounds of formula MI, wherein Y 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, t-butyllithium, tert-butyllithium and phenyllithium. Suitable proton transfer agents include sterically hindered secondary amines such as diisopropylamine and 2,2,6,6-tetramethylpiperidine. The best proton transfer agent is diisopropylamine.

Suitable inert solvents include diethyl ether, tetrahydrofuran and 1,4-dioxane. The best i) inert solvent is tetrahydrofuran. The reaction is usually carried out at a temperature of from about -100°C to about 0°C, preferably from about -78°C to about -25°C. Compounds of formula M are usually introduced into the reaction with compounds of formula IM directly, without purification. formulas IM can be prepared by reacting a compound of formula MI with borane (Bnz or VoNbe) in an inert solvent. Borane in tetrahydrofuran is preferred. Suitable inert solvents include diethyl ether, tetrahydrofuran, and 1,4-dioxane. The preferred inert solvent is tetrahydrofuran. The He! reaction is usually carried out at a temperature of from about -107C to about 66C, preferably from about 07C to about 202C. --

Compounds of formula MI are known, e.g., they are either commercially available or can be prepared by methods known to a person skilled in the art (see, e.g., Te Spetivigu oi Neiegosussis Sotroypavz, Rigidipe apa 5 Oegimaimevz, Ragi 1, E. Kiipozbreodg , Ea., Ipiegesiepse Rybiizpegv, Ips., MU, 1960).

Compounds of formula MI can be obtained from compounds of formula MI! by methods known to a person skilled in the art.

For example, compounds of formula MI, where X represents oxygen, can be prepared from the corresponding compound of formula MI, where X represents ketone oxygen, using one of the reagents well known in this field for the preparation of oxiranes from ketones (see, e.g. , reactions indicated in 9. Magsi, "Admapsei Ogdapis ts Spetivigu" (1985) Z'Ya Edyiop, rade 1161). Compounds of formula MI wherein X is sulfur may be prepared "" from the corresponding compound of formula MI wherein X is either oxygen or sulfur using one of the methods well known in the art for the preparation of episulfides from ketones or thioketones ( see, e.g., the reactions given in ).Magsy, "Admapsed Ogdapis Spetivigu" (1985) 3'Y Edyiop, radez 866-867).(o) Compounds of formula MI! are known, e.g., they are either commercially available, or may be obtained by methods known to a person skilled in the art (see, for example,

Neiiegosusiis Zuvietv m/yyp Vgiddepead Migodep Aitv, Ra 2, MU.Y.MozBu, Ea., Ipiegesiepse Rybiizpegv, Ips., se) MU, 1961). b 50 (B) Compounds where p is 1 and M represents M

Compounds of formula I (p - 1) can be obtained by the methods described below in scheme II or scheme PI. with"

F) name) 60 b5

Scheme II (r. : 1)

І (СНо)т (СНо)т со,В

Mr. M

ХН -х сн

ХМ (СН)а Ф (СН,)p

Orally with mouth on o

ok what

VN 2 VN Her 79 -- - -j-oe p

HNN HNN I. t (o) sn hi Noi hi op MY « | | "co

Gee)

BA -

І| OP. (Se) (СН))t OM (СНо)t And bu

Hevnsha Vyyy "

AND

G. M t s ХхН ХН

СН (СН)п У

I" x (St hi 7? her shk (se) b 50

I" (F ko bo b5

Uenot usna Mu vn - bu zdar ra 7 y y ----- 2A A hom H M 1 (Snip (Snip

Their

AND

/5 Scheme Pi (СНа)t (СНо)t 2 b

Gee M write what--

A -k

Y I HNN p

СН.)п (СН))п 2v ХМ ху СН» bridge? o « «co /v -A /v-- А F (СНо)t В, M (СНут r И «- шт щещи И«о)

M - - he M i. AND

ХН ХН « (СНо)п (СНо)п 8 s with ХМ ХМ (22) -

SNt about (SNI) and I -k

F M s:

And" | SA t

Kh M

(SN.) p

GF! And where Compounds of formula I, where MU represents H" and P is 1, can be obtained by deprotection of compounds of formula IX using an acid in a suitable solvent. Suitable acids include 60 mineral, organic and Lewis acids such as hydrochloric and hydrobromic acids, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid and boron trifluoride etherate. The preferred acid is hydrobromic acid. Suitable solvents include acetone, butanone, ethanone and pinacolone. The best solvent is acetone. The reaction is usually carried out at a temperature of from about -1072 to about 100°C, preferably from about 0°C to about 60°C. Alternatively, deprotection can be accomplished by heating the borane complex in alcohol solvents. The best method is boiling by refluxing a solution of the complex in ethanol.

Compounds of formula I, where MU is O and p is 1, can be obtained by oxidation of compounds of formula I, where M/ represents H» and p is 1, using selenium dioxide or by reacting first with M-bromosuccinimide, then with sodium bicarbonate and methyl sulfoxide followed by removal of the borane group as described above.

Compounds of formula I, where MU - P" and P is equal to 1, can be obtained from compounds of formula I demM - O and p is equal to 1, by reaction with diethylaminosulfur trifluoride.

Compounds of formula IX can be obtained by cyclization of compounds of formula X, where I represents fluorine, chlorine, bromine, iodine, -OSN», -ZRI, -ZSN3, -502RI or -505CH»3, in the presence of a base in an inert solvent. Suitable /0 bases include sodium hydride, sodium amide, potassium hydride, potassium tert-amylate, potassium tert-butoxide and potassium bis(trimethylsilyl)amide. The best base is sodium hydride. Suitable inert solvents include

M,M-dimethylformamide, M-methylpyrrolidin-2-one, ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane, and dimethylsulfoxide. The best inert solvent is M,M-dimethylformamide. The reaction is usually carried out at a temperature of from about -10°C to about 100°C, preferably from about 207°C to about /5866.

Compounds of formula X, where | represents fluorine, chlorine, bromine, iodine, -OSH z, -"ZRY, -ZCHz, -502RP or -5BO»CH", can be obtained by the reaction of a compound of the formula XI with a compound of the formula Y, where I is as defined above, in inert solvent. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1,4-dioxane. The best inert solvent is tetrahydrofuran. The reaction is usually carried out at a temperature of from about -100°C to about 0°C, preferably from about -78°C to about -2576.

Compounds XI, where P represents -"502RP, -5О5РІСН3, -BO»СН3 or -BO»СЕ3, can be obtained from compounds

XII reaction with a reagent such as toluenesulfonyl chloride, methanesulfonyl chloride /--: or trifluoromethanesulfonyl chloride in the presence of an amine base such as triethylamine, dimethylaminopyridine or diazabicyclo(4.3.O)nonane in an inert solvent. Suitable inert solvents can be dichloromethane, chloroform, tetrahydrofuran, diethyl ether or dioxane. The best inert solvent is dichloromethane. The reaction is usually carried out at a temperature of from about -107C to about 66C, preferably from i) about 0C to about 20C.

Compounds XI can be obtained from compounds of formula XII by reduction with such reagents as lithium aluminum hydride, sodium bis-(2-methoxyethoxy) aluminum hydride, sodium or lithium triethylboride, lithium tri-tert-butylborohydride, potassium tri-tert-butylborohydride, tri- sodium t-butylborohydride or lithium borohydride. The best reagent is sodium borohydride. Suitable inert solvents include diethyl ether, ise) tetrahydrofuran and 1,4-dioxane. The best inert solvent is tetrahydrofuran. The reaction is usually carried out by Ge! at a temperature of from about -787°C to about 66°C, preferably from about -107°C to about 2070°C.

Compounds of the formula Xi, where K represents C - C 1 -alkyl, -CHNoO-Ag or Ag, where Ag represents phenyl, -- optionally substituted by one to three of the following substituents: halogen, C 4-C/-alkyl or C .i-C,-Alkoxy, "o can be obtained by the reaction of compounds of formula XIM with borane (BH"z or BoHb) in an inert solvent. Borane in tetrahydrofuran is preferred. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1,4-dioxane. The best inert solvent is tetrahydrofuran. The reaction is usually carried out at a temperature from about -107C to about 66C, preferably from about 07C to about 2070.

Compounds of the formula CHM are known, for example, they are either commercially available or can be obtained from compounds of the formula MI! methods known to a specialist in this field for obtaining complex B-hydroxyesters. by the reaction of complex esters and ketones (see, for example, the reactions indicated in .). Magsi, "Admapseid Ogdapis "» Spetivighu" (1985) Z'YA Eaiiop, rade 439).

Compounds of the formula I, where MU represents H" and p is equal to 1, can be obtained by cyclization of the compound of the formula

XM, where Y represents fluorine, chlorine, bromine, iodine, -OSN»z, -ZRY, -ZSN»z, -80oRPY or -BO»CH»z, in the presence of a base

Ge") in an inert solvent. Suitable bases include sodium hydride, sodium amide, potassium hydride, potassium tert-amylate, potassium tert-butoxide and potassium bis(trimethylsilyl)amide. The best base is sodium hydride. Suitable inert solvents include M,M-dimethylformamide, M-methylpyrrolidin-2-one, ethers such as diethyl ether, (Ce) tetrahydrofuran and 1,4-dioxane and dimethylsulfoxide. The best inert solvent is M,M-dimethylformamide.

The reaction is usually carried out at a temperature from about -107C to about 100"C, preferably from about

Fo 20"C to approximately 66"C.

Chl» Compounds of the formula CHMI, where I as defined above can be obtained by catalytic hydrogenation of a compound of the formula CHMI using catalysts such as palladium on carbon, palladium hydroxide on carbon, palladium oxide, platinum on carbon, platinum oxide, Raney nickel or rhenium on coal, in an inert solvent.

Suitable inert solvents include methanol, ethanol, aqueous methanol or ethanol and ethyl acetate. The best solvent is ethanol. The reaction is usually carried out at a temperature from about 0"C to about 100"C,

Ф, preferably from about 207C to about 50"C. Compounds of the formula CHMI, where I. as defined above, can be prepared by reacting a compound of the formula XM with a compound of the formula XM! using a palladium catalyst together with a suitable ligand, base and bo 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, diisopropylamine, sodium carbonate or tetrabutylammonium acetate.

Suitable solvents include dimethylformamide or acetonitrile. The reaction is usually carried out at a temperature of from about 0"C to about 140"C, preferably from about 207C to about 8570. 65 Compounds of the formula HMI, where | as defined above, and K 2 represents fluorine, chlorine, bromine, iodine, trifluoromethylsulfonyl, toluene sulfonyl, or methylsulfonyl, may be prepared by literature methods from commercially available materials.

Compounds of formula XM can be prepared from compounds of formula MY by methods known to those skilled in the art for the preparation of allylic alcohols from ketones using vinyl metal salts such as vinyl magnesium bromide. (C) Compounds where P is 0 or 1

Compounds of formula I, wherein B, B3, or B" is halogen, may be prepared from compounds of formula I, wherein the corresponding substituent is hydrogen, by reaction with a suitable halogenating agent, e.g., bromine, in acetic acid. The addition of an acid catalyst may be necessary for the conversion. , such as the corresponding 70 ferric trihalide.

Compounds of formula I, where c, bz, or c" represents C 4 -C 4 alkyl, C 4 -C 4 -alkenyl, C 2 -C alkynyl, aryl, heteroaryl, can be obtained from compounds of formula I, where the corresponding substituent represents halogen or

O5OOSEZ, by reaction with a suitable reagent, an alkyl, alkenyl, alkynyl, aryl, or heteroarylstannate, in the presence of a suitable organometallic catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, e.g., 1,2-dimethoxyethane .

Compounds of the formula I, where B, B3 or B" represents aryl, heteroaryl, can be obtained from compounds of the formula

And, where the corresponding substituent is halogen or О5О оСЕ3, by reaction with an aryl- or heteroarylboronic acid in the presence of a suitable organometallic catalyst, for example, tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, for example, 1,2-dimethoxyethane.

Compounds of formula I, where K2, KZ or VK" represents MO", can be obtained from compounds of formula I, where the corresponding substituent is hydrogen, by nitration using a suitable nitrating agent, for example, nitric acid in concentrated sulfuric acid.

Compounds of formula I, where BK2, KZ or BK" represents MH", can be obtained from compounds of formula I, where the corresponding substituent represents MO 5, by reduction using a suitable technique, for example, with hydrogenation. Hydrogenation can be carried out by reacting the compound dissolved in a suitable solvent, with gaseous (In hydrogen in the presence of a suitable catalyst. Suitable solvents include methanol, ethanol and acetic acid. Suitable catalysts include palladium, e.g. 1095 palladium on carbon.

Compounds of formula I, where B2, BZ or 7 represents MER, where C represents alkyl, can be obtained from "compounds of formula I, where the corresponding substituent represents MNE, by a suitable alkylation technique. In addition, compounds of formula I, where K2, BZ or B? represents ME ZV, where VZ and KZ represent identical alkyl groups or KE? and KZ together represent (CH 2 ) B (SNI) K, can be obtained from compounds of formula I, where the corresponding /F) substituent represents BINg, by a suitable alkylation technique. Suitable alkylation techniques may include treatment with a suitable alkyl halide or sulfonate ester and a base, for example sodium hydride, in a suitable solvent, for example DMF, or treatment with a suitable aldehyde or ketone in the presence of an acid catalyst, for example zinc chloride, a reducing agent, for example, sodium cyanoborohydride, and a solvent, for example, ethanol.

Compounds of formula I, where K2, BZ, or KE" represents O5O25CE3, can be obtained from compounds of formula I, where "the corresponding substituent is OH, by reaction with trifluoromethanesulfonic anhydride in the presence of a suitable base, for example, 2,6-di-tert-butylpyridine, in a suitable solvent, for example, dichloromethane. - c Compounds of formula I, where VK, EZ or B? represents MAV, can also be obtained from compounds of formula I, "» where the corresponding substituent is a halide or О5025Сеz, by substitution with a suitable amine MNK zr, " Suitable techniques include nucleophilic substitution, which involves treatment with an amine, in excess or in the presence of an added base, and a suitable solvent, such as DMSO, or organometallic complex-catalyzed substitution, which involves treatment with an amine in the presence of a suitable organometallic

Me complex, for example, palladium complexes with chelating phosphine ligands, as described in .). Ogud Spet., - 1996, miI.61, year 7240.

Compounds of formula I, where B2, BZ, or E7 represents MES(OB", can be prepared from compounds of formula I, where o is the corresponding substituent MH 5", by suitable acylation techniques. Suitable techniques for acylation of (o) 50 include treatment with carboxylic acid chloride KUS (O)CI in the presence of an optional nucleophile

HT" of a catalyst such as 4-(M,M-dimethylamino)pyridine, a base such as pyridine or triethylamine, and a suitable solvent such as tetrahydrofuran, or alternatively treatment with a carboxylic acid

B5C(0O)CI with a coupling agent, for example, 1,3-dicyclohexylcarbodiimide, in a suitable solvent, for example, tetrahydrofuran.

Compounds of formula I, where B2, BZ or E7 represents ME "C(OMNEZ), can be obtained from compounds of formula I,

F, where the corresponding substituent is MNE, by treatment with a suitable KZMSO isocyanate in a suitable solvent, such as tetrahydrofuran.

Compounds of formula I, where 2, EZ or B? represents MAE C(FOOR, can be obtained from compounds of formula I, 60 where the corresponding substituent is MNE C, by treatment with a suitable oxychloride or carbonate in the presence of an optional nucleophilic catalyst, such as 4-(M,M-dimethylamino)pyridine, base, for example, pyridine or triethylamine, and a suitable solvent, for example, tetrahydrofuran.

Compounds of formula I, where 2, EZ or B? represents MAE502B., can be obtained from compounds of formula I, where the corresponding substituent is MNK, by treatment with a suitable sulfonyl chloride in a suitable solvent, such as pyridine.

Compounds of formula I, where 2, KZ or B" represents CM, can be obtained from compounds of formula I, where the corresponding substituent is a halide or О5О»2СЕ", by reaction with a cyanide salt in a suitable solvent with the addition of possibly also a suitable catalyst. Suitable cyanide salts include copper(I) cyanide,

Sodium cyanide, sodium dicyanocuprate, or potassium cyanide, and suitable solvents include M,N-dimethylformamide, dimethylsulfoxide, or pyridine. Catalysts that can facilitate the transformation include copper(I) oxide, tetrakis(triphenylphosphine)palladium(0), or nicol(0) complexes, which yield ips with dibrombis(triphenylphosphine)nickol(I!), zinc, and triphenylphosphine.

Compounds of formula I, where K?, KZ or BC? represents OH, OS 4-Su-alkyl, can be obtained either from 70 corresponding substituted 2-chloropyridine, or by chemical transformation from another substituent, for example,

The OH-derivative can be obtained from the MNO-derivative via a diazo intermediate.

If necessary, hydroxy, amino or other reactive groups can be protected using a protecting group, as described in the standard guide "Rhoyesipd Ogopre ip Ogdapis Zupipeviv", 2 74 Eayop (1991) Bu

Ogeepe apa MUtsiv.

Compounds of the formula | can be prepared from other compounds of formula I using general methods known to those skilled in the art for interconversions of functional groups (see, for example, the reactions given in U. Magsi, "Admapseid Ogdapis Spetivigu" (1985) Z'Ya Ediyop) .

In addition, several substituted compounds of the formula | can be obtained using an appropriately substituted compound of the formula MIP, namely 2-chloro-5-trifluoromethylpyridine will give a compound where KZ represents CEz.

The above reactions, unless otherwise specified, are usually carried out at a pressure of from about one to about three atmospheres, preferably at atmospheric pressure (near one atmosphere). Unless otherwise specified, the above reactions are carried out in an inert atmosphere, preferably in a nitrogen atmosphere.

Compounds of the invention and intermediate products can be isolated from their reaction mixtures by standard techniques. with

Acid addition salts of the compounds of formula I! which may be mentioned include salts of mineral acids, eg, hydrochloride and hydrobromide salts, and salts formed with organic acids such as formate, acetate, maleate, benzoate, tartrate and fumarate salts.

Acid-addition salts of compounds of formula I! may be formed by the reaction of the free base or salt, enantiomer or protected derivative thereof, with one or more equivalents of a suitable acid. The reaction can be carried out with a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is insoluble, such as water, dioxane, ethanol, tetrahydrofuran or diethyl ether or solvent mixtures which can be removed in vacuo or freeze drying. The reaction can be carried out metathetically (exchange reaction) or it can be carried out on an ion exchange resin. "--

Compounds of formula I exist in tautomeric or enantiomeric forms, all of which are included in the volume

From this invention. Different optical isomers can be isolated by separating a racemic mixture of compounds using commonly accepted techniques, for example, fractional recrystallization or chiral HPLC.

Alternatively, individual enantiomers can be obtained by reacting suitable optically active starting materials under reaction conditions that cannot cause racemization. " (Y) Compounds where U represents MO - 70 Compounds of the formula I, where U represents MO, X represents oxygen, A represents C(B. 2), C represents C(VU) and O represents C(B 7), can be obtained from compounds of the formula XIX, where X represents oxygen, A;" represents C(B 2 ), C represents C(B C ) and O represents SIV"), by reduction with a suitable reducing agent under suitable conditions, for example, sulfur dioxide in ethanol at room temperature.

XIX

F x M and | (Sno)t

M S t A - t» ho TMx (СН)p (. o

HF) Compounds of formula XIX can be obtained from compounds of formula I, where M represents M, X represents 7 oxygen, A represents C(E ), C represents C(E ) and O represents C(B 7 ), by oxidation with a suitable oxidant under suitable conditions, for example, with aqueous hydrogen peroxide in acetic acid at the temperature of phlegm. Compounds of the formula I, where U represents M, X represents oxygen, A represents C(B2), C represents SIV) and O represents C(B7), can be obtained similarly to the above sections (A), (B) and (C ).

Compounds of formula I, where U represents M, X represents oxygen, A represents SK 2), where b2 represents hydroxyl, can be obtained from compounds of formula I, where XU represents MO, by rearrangement using carboxylic acid anhydride in a suitable solvent, for example, trifluoroacetic acid anhydride in DMF. 65 Compounds of formula I, where U represents M, X represents oxygen, A represents SK 2), where 82 represents halogen, can be obtained from compounds of formula I, where U represents MO and A represents C(B 2 ), where B?

represents hydrogen by reaction with phosphorus halide or oxyhalide, either undiluted or with a suitable cosolvent, for example, undiluted phosphorus oxychloride.

Compounds of formula I, where Y represents M, A represents C(B2), where B? represents SM, can be obtained from compounds of formula I, where U represents MO and A represents C(B 2 ), where B? represents hydrogen by reaction with a suitable cyanide source such as trimethylsilyl cyanide in the presence of a suitable base such as triethylamine in a suitable solvent such as acetonitrile.

Intermediate products

A further aspect of the invention relates to novel intermediates. Particularly interesting among these 70 new intermediates are the borane-containing compounds, especially the compound of formula II in scheme I and the compound of formula XII! in scheme II. These intermediates can be used in the synthesis of compounds of formula I, but their use is not limited to the synthesis of said compounds.

So, for example, compounds of the formula HER

Go to sleep!

IN;

Va", VI mus

And r

X M t (Snoop where p is equal to 0 or 1, Ge! t is equal to 0 or 1, or p is equal to 0 or 1,

X represents oxygen or sulfur,

M represents oxygen, H» or P»

A represents M or C(B2), "I

C represents M or C(KU), "co

O represents M or C(B7), provided that no more than one of A, c and O represents nitrogen, and in! represents hydrogen or C1-C1-alkyl, h c, C and c" represent, independently, hydrogen, halogen, C 4-C;-alkyl, Ce-C;-alkenyl, Co-C;-alkynyl, aryl, "co heteroaryl, OH, OS.-Cu-alkyl, CO", -SM, -MO", -MA?VU, -SEz, -О50оСеz or B? and BZ or BZ and in, respectively, can together, with the participation A and C or o and 0, respectively, form another six-membered aromatic or heteroaromatic ring, which contains from zero to two nitrogen atoms and is substituted, independently, by one or two of the following substituents: hydrogen, halogen, C-C;-alkyl, Co -C,;-alkenyl, Co-Su;-alkynyl, aryl, heteroaryl, OH, « 40. OsC1-Cu-alkyl, CO», -SM, -MO», -MA?VE, -SEz, -О80» CEz, 2 with 2? and 25, independently, represent hydrogen, Ci-Su-alkyl, CO)", C(O)MNA?, C(FOORVU, 805879 or can "together be (CHguO(CH, where O represents 0, 5, MA or connection, " | equals a number from 2 to 7,

K is equal to a number from 0 to 2, 2", 88, VU, vo and KE"! represent, independently, C.4-Cu-alkyl, aryl or heteroaryl, or their enantiomers.

Me, Compounds of the formula ЧП - о (СН)т бу 0 ВН

T" co

ХхН (СН.)p

F! ЧП where о n is equal to 0 or 1, т is equal to 0 or 1, 60 X represents oxygen or sulfur, in! represents hydrogen or C.-C.-alkyl,

K represents C.4-Cv-alkyl, -CH»-Ag or Ag,

Ag represents phenyl, optionally substituted with the following substituents from one to three: halogen,

C.-C.-alkyl or C.-C.-alkyl, or their enantiomers. because Intermediates also exist in enantiomeric forms and can be used as purified enantiomers,

racemates or mixtures.

The use of compounds IM, IP, Ii, XII, X and IX as intermediates in the synthesis of a ligand for nicotinic acetylcholine receptors represents another aspect of this invention.

A further aspect of the invention relates to the use of compounds of formula I, where M represents MO, as intermediates. These intermediates can be used in the synthesis of compounds of formula I, where U represents M, but their use is not limited to the synthesis of said compounds.

Pharmaceutical compositions

A further aspect of the invention relates to a pharmaceutical composition for the treatment or prevention of a condition or 7/0 disorder, as exemplified below, resulting from dysfunction of nicotinic acetylcholine receptor neurotransmission in a mammal, preferably a human, which comprises an amount of a compound of formula I, an enantiomer thereof or its pharmaceutically an acceptable salt effective for the treatment or prevention of such disorder or condition, and an inert pharmaceutically acceptable carrier.

For the above applications, the dose administered will, of course, vary depending on the compound being used, the route of administration, and the desired treatment. However, of course, satisfactory results are obtained when the compound of the invention is administered at a daily dose of from about 0.1 mg to about 20 mg per kg body weight of the mammal, preferably in divided doses, from 1 to 4 times per day or in a sustained release form. . For humans, the total daily dose is in the range of from 5mg to 140Omg, preferably from 1Omg to 10Omg, and standard dosage forms suitable for oral administration include from 2mg to 1400mg of the compound mixed with 2O solid or liquid pharmaceutical carrier or diluent.

The compounds of formula I or their enantiomers and their pharmaceutically acceptable salts can be used as such or in the form of suitable medicinal preparations for enteral or parenteral administration. According to a further aspect of the present invention there is provided a pharmaceutical composition comprising preferably less than 80595 and preferably less than 5095 by weight of the compound of the invention in admixture with an inert pharmaceutically acceptable diluent or carrier.

Examples of diluents and carriers are: i) - for tablets and dragees: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose; - for solutions for injections; water, alcohol, glycerin, vegetable oils; for suppositories: natural or hydrogenated oils or waxes.

A method of obtaining such a pharmaceutical composition is also proposed, which includes mixing the ingredients. Gee!

Utility

Another aspect of the invention is the use of a compound of the present invention, an enantiomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product for the treatment or prevention of one of the above diseases or conditions, and a method of treatment or prevention of one of the above diseases or conditions, which includes administering to the patient a therapeutically effective amount of a compound of the invention, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

The compounds of this invention are agonists of nicotinic acetylcholine receptors. Without going into theory, it is believed that agonists of the pACyC (nicotinic acetylcholine receptor) subtype should be useful for the treatment or prevention of psychotic-type and intellectual-impairment-type disorders and have advantages over compounds that are also subtype agonists p7 pASIK. Therefore, compounds that are "" selective for the PASNIK subtype 47 are preferred. The compounds of the invention are indicated as pharmaceutical agents, particularly, for the treatment or prevention of psychotic disorders and impairments. Examples of psychotic disorders include schizophrenia, mania, and manic depression. and (o) anxiety. Examples of impairment-type disorders include Alzheimer's disease, learning disabilities, cognitive impairment, attention deficit, memory loss, and attention-deficit hyperactivity disorder. The compounds of the invention may also be used ( Se) as analgesics in the treatment of pain (including chronic pain) and in the treatment or prevention of Parkinson's disease, Huntington's disease, Tourette's disease and neurodegenerative disorders in which there is loss of cholinergic synapses. These compounds may further be indicated for the treatment or prevention of the disorder c" of a normal circadian rhythm, for use in inducing smoking cessation and for the treatment or prevention of nicotine addiction (including addiction resulting from the action of products containing nicotine).

It is also believed that the compounds of this invention can be used for the treatment and prevention of non-specific ulcerative colitis.

Pharmacology o The pharmacological activity of the compounds of the invention can be evaluated in the tests presented below: i) Test A - Analysis of affinity to the 57 PASYK subtype

Binding of 122I-y-bungarotoxin (VTX) to rat hippocampal membranes. Rat hippocampi were homogenized 60 in 20 volumes of cold buffer for homogenization (HB: concentration of components (mM): tris(hydroxymethyl)aminomethane 50; MosCl» 1; Masi 120; KSM 5; pH 7.4). The homogenate was centrifuged for 5 minutes at 1000 rpm, the supernatant was kept and the precipitate was extracted again. Collected supernatants were centrifuged for 20 minutes at 12,000 x 49, washed and resuspended in HB. Membranes (30-8Omkg) were incubated with

BNM (1295C-o-VTX, Img/ml BZA (bovine serum albumin), the test drug, and either 65 2mM Sasi" or 0.5mM ESTA |bis(p-aminoethyl ether) ethylene glycol| for 2 hours at 217С and then filtered and washed 4 times on a UUpaitap glass fiber filter (density C) using a Vgapadea cell collector. Pretreatment of the filters for 3 hours with 195 (VBA/LO, 0195 REI (polyethyleneimine)) in water was mandatory (critical for obtaining low control filters (0.079 total pulses per minute).

Non-specific binding was described using 1000 µM (-)-nicotine, and specific binding was typically 7590.

Test B - Analysis of affinity to subtype "4 pASyK

Binding of (ZNI-(-)-nicotine. Using a technique that is a modified technique of Magipo-Vatom/in and

Keijiag (Moi. Rpagt. (1987) 31:169-174), rat brain (cortex and hippocampus) was homogenized as in 70. analysis (25Ca-BTX-binding, centrifuged for 20 minutes at 12000x9, washed two times and then resuspended in HB containing 100 μM diisopropylfluorophosphate. After 20 minutes at 47°C, membranes (approximately 0.5 mg) were incubated with ZNM IZNI-(-)-nicotine, test drug, 1 μM atropine, and or 2 mM Sasi », or 0.5 mM ESTA for 1 hour at 4"C and then filtered on a glass fiber filter

U/paitap (density C) (pretreated for 1 hour with 0.595 REI) using a 75 Vgapaei cell collector. Non-specific binding was determined using 1 µM carbohol and specific binding was typically 8490.

Analysis of binding data for tests A and B

Values of ISvo and Hill's pseudo-coefficients (pn) were calculated using the program for fitting nonlinear curves of AG RIT (Oyeei eap A., Mypsop R.). apa Kodraga 0. (1977) At. 9. RNUzio!., 235:E97-E102). Saturation curves were fitted for a univariate model using the nonlinear regression program EM2RITTEK (Geashegrat, V.). (1987)), giving Co values of 1.67 and 1.70 nM for 71292-04-VTX and |ZNI-(-)-nicotinic ligands, respectively. The values of K were calculated using the general equation of Sped-Rgizoi:

CAPS wou(o n(ligandK oii)pdiuv-1) where the value n - 1 was used whenever n, « 1.5, and the value n - 2 was used when n, » s 165. Samples were analyzed in triplicate again, the values were typically zho575. Quantities K,; were determined with (3) using 6 or more drug concentrations. Compounds of the invention are compounds with binding affinities (K;) lower than 1000 nm, whether in test A or test B, indicating that they, as expected have useful therapeutic activity.

The compounds of the invention have the advantage that they can be less toxic, can be more effective, can act for a longer period of time, can have a wider range of activity, can be more potent, can cause less side effects, can be more easily absorbed or have other useful pharmacological properties. at

Examples of "--

Commercial reagents were used without further purification. Mass spectra were recorded using a 325 mass spectrometer with either a Nemiay Raskaga 5988A or MisgoMazz Otsaigo-1 and reported as t/72 for the original ke, molecular ion with its relative intensity. Room temperature refers to 20-25 76.

Obtaining 1

Complex spiro|1-azabicyclo|2.2.2|octane-3,2'-oxirane|-M-borane «

A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2 mmol) and a dispersion of sodium hydride (6095 in oil, 3.00 g, - 750 mmol) in anhydrous dimethyl sulfoxide is stirred at room temperature under a nitrogen atmosphere for 30 minutes. Then quinuclidin-3-one (7.05 g, 56.3 mmol) is added in parts in the solid state, and the mixture,

The mixture obtained is stirred at 65-707C in a nitrogen atmosphere for 1 hour. The reaction mixture is cooled, water (200 ml) is added, and the resulting solution is extracted with chloroform (3x20 ml). Extracts in chloroform are combined and reversely extracted with water (4 x 200 ml). The chloroform layer was then dried (Ma5O)), filtered and evaporated under reduced pressure to give spiro|1-azabicyclo(|2.2.2)octane-3,2'-oxirane) (6.51g, 46.8 mmol), b 8390 ) in the form of a transparent, colorless liquid. To a solution of spiro|1-azabicyclo|2.2.2|octane-3,2'-oxirane|. A solution of borane in tetrahydrofuran (1.0 M, 38.1 ml, 38.1 mmol) is added dropwise to anhydrous tetrahydrofuran (10 Oml), which is stirred at 0 "C, and the resulting solution is stirred at 07 "C in a nitrogen atmosphere for 30 minutes. Carefully add a saturated saline solution (1OOml) and an aqueous solution to the reaction solution

Gee! 20 the resulting mixture is extracted with ethyl acetate (2 x 100 ml). The organic extracts are combined, dried (Ma5O"), filtered and evaporated under reduced pressure to give the title compound (4.3g, 28.1 mmol, 7490) in 1" in; in the form of a white solid product: MS with electrospray 152 (IM-NI, 15).

Receipt 2

Complex 3-(2-chloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo|2.2.2)octane-M-borane 59 Phenyllithium solution (1.8M in a mixture of cyclohexane//light ether I7:3), 16b7ml , 0.3 mol, Zeq.) are added everywhere

HF) cannula to anhydrous tetrahydrofuran (3350ml) at -60"С in a nitrogen atmosphere. Then 7 actions of isopropylamine (0.7ml, 5 mmol) are added dropwise, followed by the dropwise addition of 2-chloropyridine (28.4ml, 0.3 mol, Eq.) for 10 minutes. The resulting solution is stirred at -407"C in a nitrogen atmosphere for 1.5 hours.

The solution is then cooled to -607C and a solution of the complex bo spiro|1-azabicyclo|2.2.2)octane-3,2'-oxirane|-M-borane (15.3 g, 0.1 mol) in tetrahydrofuran (7 /bml). The resulting reaction mixture is then stirred at -40"C in a nitrogen atmosphere. After 3 hours, a saturated solution of sodium bicarbonate (1500ml) is slowly added, then water (400Oml), and the resulting aqueous mixture is left to warm to room temperature. The layers are separated and the aqueous phase is extracted with ethyl acetate (3x100ml).

The organic layers are combined, dried (Ma950)), filtered and evaporated under reduced pressure. Column chromatography using silica gel and eluting with a mixture of ethyl acetate/hexanes (|С3:2)| gives the title compound as a reddish-brown product (17.5g, 65.6 mmol, 6695): electrospray MS 269 (IMNI" with Z7CI, 10), 267 (MNI" with Z9CI, 26).

Derivation 2(b)

The complex 3-(2,4-dichloropyridin-3Z-ylmethyl)-3-hydroxy-1-azabicyclo(|2.2.2|)octane-M-borane is obtained from 2.64 g (17.8 mmol) of 2,4-dichloropyridine and 1.37 g (8.95 mmol) of spiro|1-azabicyclo(|2.2.2)octane-3,2'-oxirane) in the amount of 2.42 g (9095), m.p. 1780179"C (ethyl acetate-hexane, 1.1).

Obtaining Z

Complex spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-v|pyridine|-M-borane Complex 70. З-(2-chloropyridine-3- ylmethyl)-3-hydroxy-1-azabicyclo|2.2.2)octane-M-borane (17.4 g, 65.3 mmol) is dissolved in anhydrous M,M-dimethylorramide (500 ml), the resulting solution is cooled to 0 "C in a nitrogen atmosphere and a dispersion of sodium hydride (6095 in oil, 6.55g, 163 mmol, 2.eq.) is added in portions. The resulting solution is stirred at room temperature in a nitrogen atmosphere for 16 hours. Then at 0" A saturated solution of ammonium chloride (5Oml), then ice water (50Oml) is added to C, and the resulting aqueous mixture is extracted with 75% chloroform (4x125ml). The organic extracts were combined, dried (MA 5 O 0 5 ), filtered and evaporated under reduced pressure to give an orange solid. Purification through a short silica gel column eluting with a mixture of chloroform/acetone (from 95:5 to 85:15) followed by stirring in hexanes (100 mL) and filtration gave a yellow solid (12.7 g, 55.2 mmol, 8495), the title compound: MS with electrospray 231 (IMNI", 65).

Receipt 4

Complex 3-(2-methanesulfonyloxyethyl)-3-trimethylsilyloxy-1-azabicyclo-(2.2.2|octane-M-borane (a) tert-Butyl ether 2-(3-hydroxy-1-azabicyclo|2.2.2)oct -Z-yl)acetic acid

To a solution of diisopropylamine (6b, 7ml) in tetrahydrofuran (THF) (20ml) at 0"C is added n-butyllithium (2.3M in hexanes, 20ml). The reaction mixture is stirred for 40 minutes and then cooled to -78"C. A solution of tert-butyl acetate (b, 4 ml) in THF (10 ml) was added dropwise to this CM mixture and stirring was continued for an additional 15 minutes. Quinuclidin-3-one (5g) in THF (15ml) is added dropwise to the mixture and the mixture is left to heat to 0"C for 1 hour. Water (100ml) is added to this solution, the solution is extracted twice with chloroform and the combined extracts washed once with a saturated saline solution. The resulting solution is dried over Mo5O)) filtered and evaporated in a vacuum, obtaining 9.53 g of the compound indicated in the subtitle "F" in the form of an off-white solid product. (b) Methyl ether 2-(3 -hydroxy-1-azabicyclo(|2.2.2|oct-3-yl)acetic acid Trifluoroacetic acid (40 ml) is added dropwise over 15 minutes to a solution of tert-butyl ether (o) 2-(3-hydroxy- 1-azabicyclo|2.2.2|oct-3-yl)acetic acid (15.7g) in anhydrous dichloromethane (40ml) at 0"C. -

The mixture is stirred for 24 hours at room temperature, then the solvent is evaporated under reduced pressure. The residue is dissolved in methanol (9 Oml) and cooled in an ice bath. Concentrated sulfuric acid is added dropwise for 10 minutes (Ce), then the reaction mixture is stirred at room temperature. After three hours, the solution is poured into 1 Oml of ice water, made basic to pH 10 with a saturated aqueous solution of sodium carbonate and extracted with chloroform (4x100 Oml). The extracts were dried (Mo5O), filtered and evaporated in vacuo to give a solid product. Recrystallization from ethyl acetate gave 6b,3g as a reddish-brown crystalline compound of the subtitle. - c (c) Complex methyl ether 2-(3-hydroxy-1-azabicyclo|2.2.2)oct-Zyl)acetic acid-M-borane and Borane in GTP (1M, 5.25ml) is added dropwise over 20 minutes to a solution of methyl ether "» 2-(3-hydroxy-1-azabicyclo|2.2.2|oct-3-yl)acetic acid (1 g) in anhydrous tetrahydrofuran (THF) (20 ml), which was stirred at 0"С. After 30 minutes, 20 ml of saturated saline is added, stirring is continued for an additional 30 minutes, and the layers are then separated. The aqueous layer is extracted with ethyl acetate (o) (2x20ml), the organic layers are combined and then dried (M9505), filtered and evaporated under reduced pressure. - The residue was subjected to flash chromatography on silica gel (elution with a mixture of chloroform/acetone, 95:5) to give the title compound (90mg) as an off-white solid product. (Ce) (d) Complex 3-hydroxy-3-(2-hydroxyethyl)-1-azabicyclo|2.2.2|octane-M-borane b 50 In an atmosphere of argon lithium borohydride (2M in tetrahydrofuran, 2, bml, 5, 2 mmol) is added for 5 minutes to the solution of the complex methyl ester 2-(3-hydroxy-1-azabicyclo|2.2.2|oct-3-yl)acetic acid-M-borane (g, chz» 4.7 mmol) in anhydrous tetrahydrofuran (2Oml) and heated under reflux for 1 hour. The reaction mixture is cooled (ice bath), quenched with water (b5ml) and saturated aqueous sodium bicarbonate (5ml), stirred for 45 minutes at a temperature from 0"C to room temperature and extracted four times with ethyl acetate. The combined organic layers are dried (Ma95O) ), evaporated under reduced pressure and triturated with ethyl ether, obtaining the title compound (80 mg, 4.5 mmol, 95965) as a white solid. trimethylsilyloxyethyl)-1-azabicyclo|2.2.2)octane-M-borane

In an argon atmosphere, chlorotrimethylsilane (0.255 ml, 2 mmol) is added through a syringe over 5 minutes to 60% of the 3-hydroxy-3-(2-hydroxyethyl)-1-azabicyclo|2.2.2)octane-M-borane complex (185 mg, 1 mmol) ) in dry 1-methylimidazole (ml) at 0"C. M-(trimethylsilyl)acetamide (262 mg, 2 mmol) is added in one portion, the reaction mixture is stirred for 16 hours at room temperature and heated at 55-607C for 3 hours The mixture is cooled, poured into a mixture of ice/water (5g) and extracted four times with ether.

The combined organic layers were washed four times with saturated saline, dried (Ma5O)), evaporated at 65°C under reduced pressure and purified by flash chromatography (elution with a mixture of hexane/ethyl acetate, 3:2) to give the title compound (210mg, 0, 64 mmol, 64906),

(e) Complex 3-(2-hydroxyethyl)-3-trimethylsilyloxy-1-azabicyclo(2.2.2)octane-M-borane in an argon atmosphere complex

3-trimethylsilyloxy-3-(2-trimethylsilyloxyethyl)-1-azabicyclo|2.2.2|octane-M-borane (190 mg, 0.58 mmol) in anhydrous methanol (mL) containing 0.032 M potassium carbonate in methanol (0 , 25 ml) are stirred at room temperature for 84 hours, acidified to pH 7 with acetic acid and evaporated under reduced pressure.

Purification by flash chromatography (elution with a mixture of hexane/ethyl acetate, 3:2) gave the title compound (94 mg, 0.37 mmol, 63905). (g) Complex 3-(2-methanesulfonyloxyethyl)-3-trimethylsilyloxy-1-azabicyclo|2.2.2|octane-M-borane 70 In an argon atmosphere methanesulfonyl chloride (0.08 bml, 1.1 mmol) in anhydrous pyridine (1 ml ) is added for 20 minutes at es - 5 to a solution of the complex 3-(2-hydroxyethyl)-3-trimethylsilyloxy-1-azabicyclo|2.2.2|octane-M-borane (257 mg, 1 mmol) in anhydrous pyridine (4 ml), stir at 07C for 20 minutes and at room temperature for 2 hours.

Pour into ice (15 g), extract four times with ethyl acetate, combine the organic layers and wash 7/5 sequentially with 1 N aqueous hydrochloric acid (three times), water and saturated aqueous sodium bicarbonate.

The extracts were dried (Ma5O)), evaporated under reduced pressure and purified by flash chromatography (elution with a mixture of chloroform/ethyl acetate, 97:3) to give the title compound (26 µg, 0.78 mmol, 78965).

Preparation of 5 (a) 3-Ethenyl-3-hydroxy-1-azabicyclo|2.2.2)octane

In an argon atmosphere, a solution of 3-quinuclidinone (1.25 g, 10 mmol) in anhydrous tetrahydrofuran (10 ml) is added over 15 minutes to a 1 M solution of vinylmagnesium bromide in tetrahydrofuran (20 ml, 20 mmol) at a temperature of

OC to 5"7C, stirred at room temperature for 24 hours, cooled to 0"C and acidified to pH 1 with 6M hydrochloric acid. The mixture is stirred for 15 minutes, made basic to pH 10 with 2590 aqueous sodium hydroxide, extracted with chloroform (4x5Oml) and a mixture of chloroform/methanol (4:11, 50 ml), organic layers are combined, dried (M950)), evaporated under reduced pressure and purified by flash chromatography (elution with a mixture of ammonia-saturated chloroform//l-ethanol, 85:15), obtaining the title compound i) (83 Ωg, 5.4 mmol, 54905). (6) 3-Bromo-2-hydroxypyridine

A solution of bromine (9.6 g, 60 mmol) in 1 M aqueous potassium bromide (120 ml) was added over 5 minutes to a solution of 2-hydroxypyridine (5.77 g, 60 mol) in 1 M aqueous potassium bromide (60 ml) and stirred. within 24 hours.

The solid precipitate is separated by filtration, the aqueous phase is saturated with sodium chloride and extracted with chloroform (4x20 ml), the combined extracts are dried (M950)), evaporated under reduced pressure and combined with He! initial sediment. Purification by flash chromatography (elution with a mixture of ammonia-saturated chloroform/methanol, 95:5) and recrystallization from acetonitrile gave the title compound (3.62 g, 20.8 --

Coll. MMOL, 3590). Ge (c) 3-Bromo-2-methoxypyridine

In an argon atmosphere, a mixture of 3-bromo-2-hydroxypyridine (3.49 g, 20 mmol), silver carbonate (3.67 g, 13.31 mmol) and iodomethane (1.5 ml, 24.1 mmol) in benzene (30 ml) is stirred in the dark at a temperature from 40"C to 50"C for 24 hours, cooled in an ice bath and filtered. The filtrate is washed once with 295% aqueous sodium carbonate and twice with water, dried (Ma5O)), benzene is evaporated at atmospheric pressure and the residue is purified by flash chromatography (elution with a mixture of hexane, ethyl acetate, 2:1), obtaining the indicated header. compound (2.35 g, 12.5 mmol, 6296). and? Example 1

Spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines

Complex /5'-spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-bB|Ipyridine|-M-borane (12.2 g, 53 mmol )

He" is dissolved in 150 Oml of acetone, the solution is cooled to 0"C and an aqueous solution of HBg (2490.5 Oml) is added. The resulting solution is stirred at room temperature in a nitrogen atmosphere for 24 hours. The reaction mixture is concentrated under reduced pressure and the aqueous residue treated with a saturated aqueous solution of sodium carbonate

Ge) (5Oml). The solution is made basic to pH » 10, using solid sodium carbonate, and the resulting solution is extracted with chloroform (3x100ml) at 5°C. The organic extracts are combined, dried (M9505), filtered and evaporated

Me, under reduced pressure to give the title compound (11.2g, 51.8 mmol, 9895, total yield 54905) in

Chl" in the form of a not quite white solid product: MS with electrospray 217 (MNI", 72).

The title compound is separated into its (K)- and (5)-enantiomers by any of the following methods:

Method A. 250 mg of the compound specified in the title is separated by chiral HPLC using column 2 5B cMmx25 cm SNIKAYSEG-O0O in the preparative chromatography system UMaiegz YuOeMa Rger 3000, eluting with a mixture of 2,2,4-trimethylpentane//ethanol (from 92908 to 9:1) at flow rate 20 ml/min. This gives 111 mg of the (5)-enantiomer o (CA)23 - 59.72 (s - 1, methanol)) and 9mg of the (K)-enantiomer (0123 - -63.92 (s « 1, methanol)). where Method B. 1 g (4.62 mmol) of the title compound is treated with I-(-)-tartaric acid (694 mg, 4.62 mmol) in 1595 aqueous ethanol (1 Oml) and recrystallized three times, obtaining I -(k) -tartrate (5)-enantiomer 60 (6BOMg, 1.77 mmol; (Fo - B), (c - 2, H2O)). The filtrates are concentrated under reduced pressure and the aqueous solution is made basic to pH » 10 using solid sodium carbonate The resulting mixture is extracted with chloroform (3x25ml) and the combined extracts are dried (M950)) and evaporated under reduced pressure. The residue (6b5Omg,

C mmol) treated with O-(-)-tartaric acid (452 mg, C mmol) and recrystallized as described above to give O-(-)-tartrate of the (P)-enantiomer (775 mg, 2.11 mmol; (0129 - -58.22 (c - 2, NgV)) because Example 2A

5-Bromospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-v|Ipyridine| A solution of spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo2,3-B|pyridine| (1OOmg, 0.462 mmol) and sodium acetate (41Omg, mmol) in 5095 aqueous acetic acid (4ml) is heated to 60°C. Bromine 5 (0.100ml, 1.94 mmol) is added through a syringe over 10 minutes, and the solution is then heated under reflux for 1 hour.

The mixture is left to cool to room temperature, made basic to pH » 10 with sodium carbonate and extracted with chloroform (3 x 5 ml). The combined extracts were dried (M950)), filtered and evaporated under reduced pressure to give the title compound (110mg, 0.37mmol, 8195) as an off-white solid: electrospray MS 295 (IMNI), with " UVg, 100), 297 (MH, z8'Vg, 98). 70 Example 28 (KO-(-)-5-Bromospiro|1-azabicyclo|2.2.2|octane-3,2-(3'H)-furo|2,3-bipyridine| Enantiomer, (KO-(-) -spiro|1-azabicyclo|2.2.2octane-3,2-(3'H)-furo|2,3-b|Ipyridine)| (1.95 g, 9 mmol) was treated in the same way as described in example 2A , gives the title compound (1.77g, b mmol, 6795) (α - -45.57 (s - 1, MeOnH)).

Example With 5-Phenylspiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-in|pyridine in a nitrogen atmosphere 5-bromospiro|1-azabicyclo|2.2.2|octane -3,2'-(3'H)-furo|2,3-ypyridine (118 mg, 04 mmol), phenylboronic acid (54 mg, 0.443 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 2.3 mol .b5) are mixed in a solution of 1,2-dimethoxyethane (3 ml) and ethanol (0.75 ml) containing 2M aqueous sodium carbonate (0.65 ml, 1.3 mmol). The mixture is heated at reflux for 18 hours. The reaction mixture is then evaporated under reduced pressure, the residue is dissolved in chloroform (1 bml) and the extract is washed with saturated aqueous sodium carbonate (bml). The aqueous layer is extracted with chloroform (2 x 15 ml), and the organic layers are combined, dried (M95O)), filtered and evaporated under reduced pressure. Purification by flash chromatography over silica gel eluting with a mixture of ammonia-saturated chloroform/methanol (95:5 to 9951) afforded the title compound He (8VOmg, 0.274 mmol, 6895) as a reddish-brown solid: electrospray MS at 293 (MNI", 100).

Example 4A 5-Nitrospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-b|Ipyridine|. A mixture of spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo2,3-B|Ipyridine| (325 mg, 1.5 mmol) and fuming nitric acid (0.27 ml, 5.74 mmol) in sulfuric acid (0.75 ml) is heated at a temperature from 707C to 807C for 24 hours. The resulting viscous solution is poured onto 15 g of ice and adjusted to a pH of 10 with solid sodium carbonate. The resulting mixture is extracted with chloroform (4x15 ml), dried (Mo5O)), filtered (F) and evaporated under reduced pressure. Purification by flash chromatography over silica gel eluting with ammonia-saturated chloroform/methanol (95:5) gave the title compound (200 mg, 0.765 mmol, 51905) as a pale yellow solid: electrospray MS 262 (IMNI) , 100). ise)

Example 48 (KO)-(-)-5-Nitrospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine (KO-(-)-Spiro |1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-B|Ipyridine (3.03 g, 14 mmol) was dissolved in concentrated sulfuric acid (7 ml) at 0-57C, fuming nitric acid (3.3 ml, 70.2 mmol) is added over 10 minutes, the mixture is stirred for 1 hour and heated at 65-70 for 24 hours. of water, make basic to pH 10 with solid potassium carbonate, "" stir for 1 hour, filter and dry the solid title compound (3.6bg, 13.8 mmol, " 9895): MS with electrospray (t/27, relative intensity ) 262 (MNI", 100).

Example 4C (5)-(A)-5-Nitrospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-b|pyridine| Enantiomer, b (5)-nitrospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-bB|Ipyridine| (6b.5g, 30 mmol), treated in the same way as described in Example 48, gives the title compound (7.75g, 29.7 mmol, 9995): MO with co-electrospray (t/2, relative intensity ) 262 (|MNI", 100).

Example 5 (o) 20 Spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-BIquinolines

HT" The compound specified in the title is obtained by a method similar to the method described in example 1, from 2-chloroquinoline (0.99 g, 6.06 mmol) and the complex spiro|1-azabicyclo|2.2.2|octane-3,2'- oxirane|-M-borane (0.31g, 2.0 mmol) to give the title compound (0.135g) as a white powder, electrospray MS 267 IMNI.

These two enantiomers are separated on a Spigai OO column by elution with a gradient of a mixture of 8-1090 (F; EUN/hexane and UV-detection. The first enantiomer: 10095 chiral purity according to PH data, K ,- 12.32

GI minutes, (4|uo at 23"C in EUN - 47.9". The second enantiomer: 99.495 chiral purity, K, - 17.84 minutes, |(oSchr - -48.57. in Example 6 1-Chlorospiro| 1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo!|2,3-VIisoquinoline| of dichloroisoquinoline (2.41 g, 12.2 mmol) and the complex spiro|1-azabicyclo|2.2.2|octane-3,2'-oxirane-M-borane (0.62 g, 4.05 mmol), obtaining 0.86 g complex 1-chlorospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-Vi|isoquinoline|-M-borane, Mo with b5 electrospraying 314 |MNI". Removal of the borane group in 5mg of the M-borane complex gives 30mg of the title compound, electrospray MS 301 IMNI".

Example 7

Spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-Alisoquinoline| The borane-protected chloride of example 6 (0.3 g or 0.96 mmol) is suspended in a mixture of glacial acetic acid (b.0 ml) and water (0.5 ml). The suspension is placed in a nitrogen atmosphere and zinc dust (150 mg) is added. The reaction mixture was stirred at 707 for 5 hours. The reaction mixture is left to cool and then poured into saturated Manso with.

A sufficient amount of aqueous ManSOO» is added to achieve the basic pH value, and the products are extracted with three portions of chloroform. The combined extract in chloroform was dried (Mo5O), filtered and evaporated in vacuo. The products of the two experiments are combined for purification on a silica gel column using a gradient from /0 2:11 mixture of hexane//"ethyl acetate to 710095 ethyl acetate. The compound eluting faster is the complex spiro|1-azabicyclo|2.2.2)octane -3,2-(3'H)-furoic|2,3-B|isoquinoline|-M-borane, and the slower eluting compound is the title compound. Yield 10090: MS with chemical ionization 279 MH) - But for the M-borane complex and 267 МН) for the title compound. Removal of the borane group under the conditions of Example 1 followed by flash chromatography gives the title compound as a brown semi-solid 75 product: MS with chemical ionization 267 (МНИ".

Example 8A 5-Aminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine

A mixture of /5-nitrospiro|1-azabicyclo(2.2.2|octane-3,2-(3'H)-furo|2,3-b|Ipyridine| (1.4 g, 5.36 mmol) and 1095 palladium on of coal (4895 moisture, 27Omg) in methanol (9Oml) is hydrogenated for 1 hour at 345 kPa (5 Orvi) of hydrogen. The catalyst is separated by filtration through a celite pad and the solvent is evaporated under reduced pressure to give the amine (1.2g, 5.25 mmol, 9895 ) in the form of a reddish-brown solid product: MO with electrospray (t/g, relative intensity) 232 (MNI", 100).

The title compound is separated into (K)- and (5)-enantiomers in the following way: 1500 mg of the title compound is separated by chiral HPLC using a 2 cm x 25 cm M s SNIVACEI -O00 column in a preparative chromatography system Uiaegz Oeka Rger 4000 |hexane//ethanol (from 85:15 to 8:2)) d) at a flow rate of 20 ml/min. This gives 52 mg of (5)-epimer (077 - 622 (s - 1, ethanol) and 52 mg of (K)-epimer (od - -647 (s - 1, ethanol).

Example 88 (KO)-(-)-5'-Aminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridine)| Enantiomer, t (KO-(-)-5-nitrospiro|1-azabicyclo|2.2.2|octane-3,2-(3'H)-furo|2,3-B|Ipyridine|i (3.8g, 13.3 mmol) was treated with O in the same manner as described in Example 8A and purified by flash chromatography (eluting with ammonia-saturated chloroform/methanol, 95:5 to 85:15) to give the title compound (2, 5g, 10.8 mmol, F 8196): MS with electrospray (t/2, relative intensity) 232 МН", 100). - from Example 8C with (5)-(-)-5-Aminospiro|1-azabicyclo| 2.2.2) octane-3,2'-(3'H)-furo|2,3-B|Ipyridine) | Enantiomer, (5)-()-5-nitrospiro|1-azabicyclo|2.2.2)octane -3,2'-(3'H)-furo|2,3-BIpyridine) (6.85 g, 26.2 mmol), treated in the same manner as described in Example BA, in methanol saturated with ammonia, gives the indicated in title compound (5.55g, 24 mmol, 9290): MS with electrospray (Itp/2, relative intensity) 262 (MNI", 100). "

Example 9 2 with 5-Phenylcarboxamidospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-ypyridine in a nitrogen atmosphere benzoic acid (b7 mg, 0.55 mmol), tetrafluoroborate; t O-(1nH-benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium Stvtu", 17 mg, 0.55 mmol), 1-hydroxybenzotriazole hydrate ("NOVT", 78 mg, 0.55 mmol) ) and diisopropylethylamine (0.1933 ml, 1.1 mmol) are mixed in anhydrous M,M-dimethylformamide (vml) and stirred for 10 minutes. b 5-Aminospiro|1-azabicyclo|2.2.2)octane-3,2'- (3'H)-furo|2,3-B|pyridine) (115 mg, 0.5 mmol) was added as a solid in one portion and stirring was continued for 3 days. The solvent was evaporated under high vacuum and heated to 557 "C and the residue are distributed between saturated aqueous sodium carbonate (2 ml) and dichloromethane (1 ml). After separation, the aqueous phase is extracted with dichloromethane (2x5 ml). The organic layers are combined, dried (Ma5O)) and evaporated under reduced pressure. Purification by flash chromatography over silica gel eluting with ammonia-saturated chloroform/methanol (9:11) afforded the title compound (125 mg, 0.372 mmol, 75905) as a yellow solid: MO with electrospray (It/7 , relative intensity) 336 MN)", 100).

Example 10 5-Phenylaminocarbonylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine in a nitrogen atmosphere phenyl isocyanate (0.05 bml, 0.515 mmol) is added to a suspension of ) 5-aminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridine)| (119 mg, 0.514 mmol) in anhydrous cotetrahydrofuran (5 ml) and stirred for 12 hours. The solvent is evaporated under reduced pressure and the residue is purified by flash chromatography over silica gel eluting with a mixture of saturated ammonia and chloroform/methanol (92.5:7.5) to give the title compound (155 mg, 0.442 mmol, 86705) as an off-white of solid product: MS with electrospray (t/7, relative intensity) 351 ((MNI", 100).

Example 11 5-Phenylsulfonylamidospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine

In a nitrogen atmosphere, benzenesulfonyl chloride (0.07 ml, 0.55 mmol) was added to a solution of 65 5'-aminospiro|1-azabicyclo|2.2.2)octane-3,2-(3'H)-furo|2,3-B |pyridine) (115 mg, 0.5 mmol) in anhydrous pyridine and stirred for 4 hours. The solvent is evaporated under high vacuum, the residue is distributed between saturated aqueous sodium carbonate (2ml) and chloroform (10ml), separated and the aqueous phase is extracted with chloroform (2x5ml). The combined organic layers were dried (MABOD, the solvent was evaporated under reduced pressure and the residue was re-evaporated from ethanol (3 x 10 mL) under reduced pressure. This gave the title compound (17 µg, 0.5

MMmol, 10090) as a yellow solid product: MS with electrospray (tp/2, relative intensity) 372 (MNI", 100).

Example 12 5-(M-Methylamino)spiro|1-azabicyclo|2.2.2)octane-3,2-(3'H)-furo|2,3-B|Ipyridine| In a nitrogen atmosphere, sodium (5Omg, 2.17 mmol) is slowly added (the reaction is exothermic) to methanol (ml) and stirred for 1 hour. 70 Add 5-aminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine (115 mg, 0.5 mmol) and paraformaldehyde (35 mg, 1.17 mmol) and stirred for 16 hours. The reaction mixture is heated at 507C for 4 hours, sodium borohydride (5 mg, 1.4 mmol) is added and heated at reflux for 1 hour. Then 1N aqueous potassium hydroxide (0.4 ml) is added and refluxing is continued for more than 2 hours. The solvent is evaporated under reduced pressure, the residue 75 is distributed between water (Tml) and chloroform (4ml), separated and the aqueous phase is extracted with chloroform (2x4ml). The combined organic layers were washed with saturated saline solution (ml), dried (MaOSO)), evaporated under reduced pressure and purified by flash chromatography throughout silica gel (eluting with a mixture of ammonia-saturated chloroform/lethanol (95:5)) to give the title compound ( 78 mg, 0.32 mmol, 6495) as an off-white solid: electrospray MS (t/z, relative intensity) 246 (IMNI", 100).

Example 13A 5-(M,M-Dimetalamino)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine

Sodium cyanoborohydride (bZmg, 1 mmol) is dissolved in methanol (2.5 ml), anhydrous zinc chloride (bomg, 0.5 mmol) is added, stirred for 30 minutes, the resulting solution is added to a solution of 5-aminospiro|1-azabicyclo /2.2.2|octane-3,2'-(3'H)-furo|2,3-B|Ipyridine| (115 mg, 0.5 mmol) and 3790 C of aqueous formaldehyde (0.12 mg, 1.6 mmol) in methanol (2.5 mL) and stirred for 20 hours. Pour to 1H aqueous potassium hydroxide (1Oml), stir for 1 hour, evaporate under reduced pressure and extract the aqueous residue with chloroform (4x1Oml). The combined extracts were dried (Ma5O)), evaporated under reduced pressure and purified by flash chromatography over silica gel (eluting with a mixture of ammonia-saturated chloroform/methanol, 97.5:2.5) to give the title compound (85 mg, 0, 33 mmol, 6bbUo) in the form of not "I completely white solid product: MS with electrospray (t/2, relative intensity) 260 (|MNI", 100). "so

Example 138 (KO)-(-)-5-(M,M-Dimethylamino)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-in|pyridine ( 22)

Enantiomer, (KO)-(-)-5'-aminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-ypyridine (231 mg, 1 «- mmol ), treated in the same manner as described in Example 13A, afforded the title compound (178 mgH, 30 0.69 mmol, 6995): Electrospray MS (t/2, relative intensity) 260 (MNI", 100). ise )

Example 14A (5)-C3)-5-(E)-(Phenylethenyl)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-in|Ipyridines

A solution of (5)-(4)-5'-bromospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-bIpyridine| (15 mg, 0.51 mmol), styrene (0.07 ml, 0.61 mmol), palladium(I) acetate (1.2 mg, 0.0053 mmol), tri-o-tolylphosphine (b, 4 mg, 0.021 - 70 mmol) and triethylamine (0.5 ml, 3.6 mmol) in anhydrous acetonitrile (0.5 ml) in a thick-walled threaded glass tube containing a magnetic stirring rod, purged with argon and sealed with a Teflon stopper and EETEE O- ring The mixture is stirred and heated at 1007C for 2 hours, cooled to room temperature, dissolved in chloroform (10ml), washed with saturated aqueous sodium carbonate (1ml), dried (M9504) and evaporated under reduced pressure. Recrystallization from ethyl acetate afforded the title compound (9Omg, 0.28 mmol, 5595) as a light reddish-brown solid: electrospray MS

Ф (t/2, relative intensity) 319 (IMNI", 100). - Example 148 so (KO-(-)-5-(E)-(Phenylethenyl)spiro|1-azabicyclo|2.2.2octane-3,2 '-(3'H)-furo|2,3-in|pyridine

Processing of the enantiomer, (K)-(-)-5'-bromospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-5|pyridine|) (o ) 20 (295 mM, 1 mmol), in the same manner as described in Example 14A, and purification by flash chromatography

GT" (eluting with a mixture of ammonia-saturated chloroform/methanol, from 98:2 to 96:4) gave the title compound (132 mg, 0.41 mmol, 4195): electrospray MS (ti/z, relative intensity) 319 ( ME", 100).

Example 15A (5)-(-)-5(4-Morpholino)spiro|1-azabicyclo|2.2.2)|octane-3,2'-(3'H)-furo|2,3-ypyridine tert-Butoxide sodium (56.bmg, 0.59 mmol), tris(idibenzylideneacetone)-dipalladium (15.4mg, 0.017 mmol) and (F) 2,2-bis(diphenylphosphino)-1,1-dinaphthyl (21mg, 0.034 mmol) mixed in a thick-walled threaded glass tube,

A GI containing a magnetic stirring rod and purged with argon. Add (5)-(-)-5-bromospiro|1-azabicyclo|2.2.2)octane-3,2-(3'H)-furo|2,3-B|pyridine)| (13Omg, 0.44 mmol), morpholine (O.0bbml, 0.76 mmol) and anhydrous tetrahydrofuran (Zml), sealed with a Teflon plug and

EETEE-O-ring, stir and heat at 1007C for 72 hours. The mixture is cooled to room temperature, dissolved in chloroform (25 ml), washed with saturated saline solution (3 x 2 ml), dried (M9503), evaporated under reduced pressure, purified by flash chromatography throughout silica gel (elution with a mixture of ammonia-saturated chloroform//methanol, 4:1 ) and recrystallized from ethyl acetate to give the title compound (35 mg, 0.12 mmol, 2695) as a reddish-brown solid: electrospray MS (t/l, relative intensity) 302 (IMNI, 100).

Example 158 (KO-(-)-5-(4-Morpholino)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-ypyridine

Treatment of the enantiomer, (KO-(-)-5-bromospiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-VIpyridine) (580 mg, 1.965 mmol), by the same method as described in Example 15A gives the title compound (187 mg, 0.62 mmol, 3295): electrospray MS (ti/, relative intensity) 302 (MNI", 100).

Example 16. -(-)-5'-Bromospiro|1-azabicyclo|2.2.2)octane-3,2-(3'H)-furo|2,3-B|pyridine)| (295 mg, 1 mmol), azetidine 70. (0101 ml, 1.5 mmol), sodium tert-butoxide (135 mg, 1.4 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 0.05 mmol), 2,2- bis(idiphenylphosphino)-1,1-binaphthyl (6b2mg, 0.1 mmol) and anhydrous tetrahydrofuran (Uml) were mixed in a thick-walled threaded glass tube containing a magnetic stirring bar, purged with argon, and sealed with a Teflon stopper and RETRE-O- ring The mixture is stirred and heated at 757C for 4 hours, cooled to room temperature, dissolved in chloroform (20ml), washed with saturated saline solution (3x10ml), dried (Ma5zO)), evaporated under reduced pressure and purified by flash chromatography throughout silica gel (elution with a mixture ammonia-saturated chloroform//methanol, 95:5) to give the title compound (230mg, 0.085mmol, 8595) as a light reddish-brown solid: MS with chemical ionization (t/2, relative intensity) 272 (MS ", 56).

Example 17 (KO)-(-)-5-(2-(4-Pyridyl)ethenyl)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-in |pyridines (KO)-(-)-5'-Bromospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines (295 mg, 1 mmol), 4-vinylylidine (0.135 mL, 1.25 mmol), palladium(I!) acetate (7.2 mg, 0.032 mmol), tri-o-tolylphosphine (38.7 mg, 0.127 mmol), and triethylamine (0.5 mL, 3, 6 mmol) in anhydrous acetonitrile (0.5 mL) is mixed in a thick-walled threaded glass tube containing a magnetic stirring bar, purged with argon, and sealed with a Teflon stopper and RGETEE O-ring. The mixture is stirred and heated at a temperature from 1007C to 1057 o for 48 hours, cooled to room temperature, dissolved in chloroform (25 ml), washed with saturated aqueous sodium carbonate (2 ml), dried (Ma9a5O)) and evaporated under reduced pressure. Purification by flash chromatography over silica gel (elution with ammonia-saturated chloroform/methanol, 95:5) followed by recrystallization from acetone gave the title compound (230 mg, 0.72 mmol, 7290): MS with chE electrospray (t/g, relative intensity) 320 (MNI|", 100). "co

Example 18 (KO-(-)-5-(2-(2-Pyridyl)ethenyl)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-ypyridine ( 22) (K)-(-)-5-Bromospiro|1-azabicyclo/2.2.2|octane-3,2'-(3'H)-furo/2,3-VIpyridine (15mg, 0.5 mmol) d- treated with 2-vinylpyridine (0.07Oml, 0.65 mmol) in the same way as described in example 16. Purification by flash chromatography throughout silica gel (elution with a mixture of ammonia-saturated simple ether//methanol, from (Ce) 95:5 to 9:1) followed by recrystallization from acetonitrile gave the title compound (37 mg, 0.12 mmol, 2395): electrospray MS (Itp/2, relative intensity) 320 (|MNI", 100).

Example 19 "(K)-(-)-5'-(-2-Trimethylsilylethenyl)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-in|pyridine (K)-(-)-5'-Bromospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridine (295 mg, 1 mmol), With c trimethylsilylacetylene (0.355 mL, 2.5 mmol), tetrakis(triphenylphosphine)palladium (23 Ωg, 0.2 mmol), triethylamine (2 mL), and anhydrous acetonitrile (2 mL) were mixed in a thick-walled threaded glass tube containing a magnetic rod, which stirs, is purged with argon and sealed with a Teflon stopper and a HETERO-O-ring. The mixture is stirred and heated at 1007C for 4 hours, cooled to room temperature, dissolved in chloroform (25 ml), washed with saturated aqueous sodium carbonate (2 ml), dried (Ma5O)) and evaporated at

Me. reduced pressure. Purification by flash chromatography all over silica gel (eluting with a mixture of saturated ammonia - ether/methanol, 9:1) gave the title compound (280 mg, 0.90 mmol, 9090): electrospray MS (t/2, relative intensity) 313 ((MNI", 30). o Example 20

He») 20 (K)-(-)-5'-Ethynylspiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-in|pyridine in an argon atmosphere 1M solution tetrabutylammonium fluoride in tetrahydrofuran (1.3 ml, 1.3 mmol) is added at 07"C to the solution

T» (KO)-(-)-5'-(-2-trimethylsilylethynyl)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-v| pyridine) (265 mg, 0.85 mmol) in anhydrous tetrahydrofuran (bml) and stirred at room temperature for 2 hours.

The reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (2 ml), extracted with ether (5 x 15 ml), dried (MazO)), evaporated under reduced pressure and purified by flash chromatography throughout silica gel

HF) (elution with a mixture of ammonia-saturated chloroform//methanol, 95:5), obtaining the title compound

HF (121 mg, 0.50 mmol, 5995): MS with chemical ionization (t/7, relative intensity) 241 (IMNGI, 19).

Example 21 5-(2-Furyl)spiro|1-azabicyclo|2.2.2)|octane-3,2'-(3'H)-furo|2,3-VIpyridines A solution containing 60 5-bromospiro|1 -azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-vIpyridine (103.5 mg, 0.351 mmol), tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol ), tri-(o-tolyl)phosphine (44.4 mg, 0.146 mmol, lithium chloride (b2 mg, 1.46 mmol) and 2-(tri-n-butylstannyl)furan (0.17 g, 0.476 mmol) in 1 ,2-dimethoxyethane (1 ml), heated at reflux for 2 hours. The solution was evaporated and the residue was dissolved in chloroform and filtered. The filtrate was evaporated, then purified by HPLC using a gradient of 0-2595 mixture bo 1:1:2 7M solution of ammonia in methanol:methanol:chloroform and chloroform to give the title compound

(89 mg, 0.313 mmol, 8995) as a tan solid product; MS with electrospray (t/7, relative intensity) 283 ((MNI", 100).

Example 22 5-(3-Pyridyl)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-in|pyridine

A solution containing 5'-bromospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridine| (158mg, 0.535mmol), tris(dibenzylideneacetone)dipalladium(0) (23mg, 0.025mmol), tri-(o-tolyl)rosphine (bbmg, 0.217mmol), lithium chloride (9Omg, 2.34mmol) and 3- (tri-n-butylstannyl)pyridine (0.2 mL, ca. 0.3 g, ca. 0.82 mmol) in 1,2-dimethoxyethane (2 mL), heated at reflux for b hours. Solution 70 is evaporated and the residue is dissolved in chloroform and filtered. The filtrate was evaporated, then purified by HPLC using a 0-20905 gradient of a 1:1:2 mixture of 7M ammonia in methanol:methanol:chloroform and chloroform to give the title compound (58 mg, 0.198 mmol, 3790) as a tan solid: MO with electrospray (t/2, relative intensity) 294 (|MNI", 80), 273 (100).

Example 23 5-Methylspiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-in|pyridine A solution containing 5-bromospiro|1-azabicyclo|2.2.2| octane-3,2'-(3'H)-furo|2,3-pyridine (203Zmg, 0.687 mmol), tris(dibenzylideneacetone)dipalladium(0) (ZZmg, 0.036 mmol), tri-(o-tolyl)phosphine (95 mg, 0.312 mmol), lithium chloride (241 mg, 5.69 mmol), and tetramethylstannane (1.0 mL, 1.3 g, 7.2 mmol) in 2-methoxyethyl ether (bBmL) are heated in a bath maintained at 100"Sb. After 3 hours, the next portion of tetramethylstannane (ml, 1.3g, 7.2 mmol) is added and heating is continued overnight. The solution is filtered and subjected to HPLC purification using a gradient of 0-209o mixture of 1:1:2 7M ammonia solution in methanol:methanol:chloroform and chloroform to give the title compound (120 mg, 0.519 mmol, 7695) as a tan solid: electrospray MS (t/2, relative intensity) 231 (MNI", 100).

Example 24 p

Spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine-5'-carbonitrile| and about sp1ro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-8|IpTridine-5'-carboxamide

A solution containing 5'-bromospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridine| (16b5mg, 0.558 mmol) and copper(I) cyanide (b0Omg, 1.3g, about 7.2 mmol) in 1-methyl-2-pyrrolidinone (ml), heated in a bath maintained at 180°C overnight and then left to cool. The solution is then partitioned "And between aqueous ammonia and chloroform and the organic layer is separated, then dried (magnesium sulfate), "so filtered and evaporated. The residue is purified by HPLC using a gradient of 0-2095 mixture of a 1:12 7M solution ammonia in methanol: methanol: chloroform and chloroform, obtaining /F) spiro|1-azabicyclo(2.2.2)octane-3,2'-(3'H)-furo2,3-in|Ipyridine-5-carbonitrile| ( 52 mg, 0.216 mmol, 3990) in the form of a tan solid product: OSI MS with electrospray (t/2, relative intensity) 242 (MNI 7, 32 100), and spiro|(1-azabicyclo|2.2.2)octane- 3,2'-(3'H)-furo|2,3-bIpyridine-5'-carboxamide| (71 mg, 0.274 mmol, 4995) ise) as a tan solid: electrospray MS (Ip/2, relative intensity ) 260 ((ME", 100).

Example 25 5-Ethenylspiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine Solution containing "5-bromospiro|1-azabicyclo|2.2.2 |octane-3,2'-(3'H)-furo|2,3-lipyridines (15mg, 0.508 mmol), - 70 tris(dibenzylideneacetone)dipalladium(0) (22mg, 0.024 mmol), tri-(o- tolyl)phosphine (bZmg, 0.206 mmol), lithium chloride (10Zmg, 2.43 mmol) and tri-n-butylvinylstannane (188mg, 0.592 mmol) in 1,2-dimethoxyethane (1Oml), heated at reflux under reflux overnight. The solution is evaporated and the residue is dissolved in chloroform and filtered. The filtrate is evaporated, then purified by HPLC using a 0-2595 gradient of a 1:1:2 mixture of 7M ammonia in methanol:methanol:chloroform and chloroform to give the title compound (9mg, 0.385 mmol, 7695) as a tan solid; MS with electrospraying (t/7, relative

F intensity) 243 ((MNI", 100). - Example 26 co (KO-(-)-5-M'(3-Chlorophenyl)aminocarbonylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-( 3'H)-furo|2,3-in|pyridine (8)-(-)-5'-Aminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo| 2,3-β|Ipyridine (bbmg or 0.28 mmol) (o) 50 is suspended in 2.7 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere. 3-Chlorophenylisocyanate (35 µL) is added and

GT" suspension is stirred at room temperature for 5 hours. Tetrahydrofuran is removed in vacuo and the crude product is purified by flash chromatography. Elution of 20-4095 with a solution of methanol/chloroform (which contains MNAOH) gives the target product. The solvents are removed in vacuo and the residue is dissolved in chloroform and dried (Ma5O)). Evaporation with two portions of ether gives 10mg (92905) of a white solid. MS with electrospray 385 and 387 IMNI". (F; Example 27

GI (KO-(-)-5-M'-(2-Nitrophenyl)aminocarbonylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|Ipyridines

Using the same method as in example 27, but replacing 3-chlorophenyl isocyanate with 2-nitrophenyl isocyanate, the title compound is obtained; yield 97 mg (88956) of yellow powder. MS with electrospray 396 IMNI".

Example 28 (KO-(-)-5'-M,M-Diethylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine

Sodium cyanoborohydride (190 mg or 3.0 mmol) and zinc chloride (20 mg or 1.5 mmol) are added to 3.0 ml of 65 anhydrous methanol under nitrogen atmosphere. Stirring for 5 minutes leads to complete dissolution.

Add (K)-(-)-5'-aminospiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-BI|Ipyridine| (23O0mg or 1.0 mmol),

then acetaldehyde (0.335 ml or 6.0 mmol). The suspension is stirred at room temperature for 16 hours. Methanol is concentrated in a vacuum and the suspension is poured into 20 ml of 0.1 N sodium hydroxide. The aqueous layer is extracted with four portions of 2000 ml of chloroform, the chloroform layers are combined, dried (Mo 50 O y) and evaporated in a vacuum. The crude product is purified by flash chromatography, starting with elution with a mixture of 6//3/1/0.1 ethyl acetate//methanol/iodine (containing MH.OH) and then with a mixture of 3//6//1//0O.1. The solvents are removed in vacuo and the residue is dissolved in chloroform and dried (Ma5zO 54). 0.227 g (7995) of light brown syrup is obtained. MO with electrospraying 288 MNI".

Example 29 70 (KO-(-)-5-M-Ethylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-in|pyridine (KO-( -)-5-Aminospiro|1-azabicycloi/2.2.2|octane-3,2-(3'H)-furo|2,3-B|Ipyridine| (2300 mg or 1.0 mmol) and sodium cyanoborohydride are suspended in b.2 ml of anhydrous methanol. Acetaldehyde (dOml or 1.1 mmol) is added and the solution is stirred at room temperature for 16 hours. The methanol is removed in vacuo and the residue is dissolved in 2 ml of water and 8 ml of chloroform. The layers are separated and the aqueous layer is extracted again 75 The combined organic layers were dried (Mo 5 O)) and evaporated in vacuo. The crude product is purified by flash chromatography using a gradient of 3-1595 methanol//chloroform (saturated with ammonia). Solvents are evaporated in a vacuum and displaced with two portions of ether. The residue is suspended in ether and collected by filtration. After washing with ether and drying in a high vacuum, 81 mg (3195) of a white powder is obtained. MS with electrospraying 260 |MNI".

Example 30 (KO-(-)-5-M-Benzylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-in|pyridine

It is obtained by the method of example 12. 247 mg (7790) of white powder is obtained from 1.0 mmol. MS with electrospray 322 |MNI".

Example 31 with (KO-(-)-5'-M-Formamidospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine o 98956 Formic acid ( 2.1 ml) and acetic anhydride (0.7 ml) are mixed in a nitrogen atmosphere and cooled in an ice bath. Add (K)-(-)-5'-aminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-b|pyridine|. (230 mg or 1.0 mmol) and the reaction mixture is left to warm to room temperature. The reaction mixture was stirred for 26 hours and then poured with stirring into saturated sodium carbonate. Solid Ma»CoO» is added until the pH becomes alkaline again, and then the aqueous layer is extracted with four portions of «SO chloroform. These layers of chloroform are combined, dried (Ma5O)) and evaporated in vacuo. The crude product is purified by flash chromatography, eluting with a gradient of 2-1095 mixture saturated with ammonia methanol//chloroform. /F)

The solvents are removed in vacuo and the residue is dissolved in chloroform, dried (Mo95O) and evaporated in vacuo. "-

The solvent was displaced with two portions of ether, yielding 0.2 g (7790) of a white solid product. MS with 3o electrospray 260 |MNI". ise)

Example 32 (K)-(-)-5-M-Acetamidospiro|1-azabicyclo(2.2.2|octane-3,2'-(3'H)-furo|2,3-ypyridine (KO-(-) -5-Aminospiro|1-azabicyclo!|2.2.2octane-3,2'-(3'H)-furo|2,3-ypyridine (230 mg or 1.0 mmol) was dissolved in 3 ml of anhydrous pyridine in a nitrogen atmosphere. Acetic anhydride (0.1 mL or 1.1 mmol) is added and the solution is heated at 1007C for 40 hours. The pyridine is removed in vacuo and the residue is dissolved in 3 mL of chloroform and washed with 4 mL of saturated sodium bicarbonate. The aqueous layer is extracted two more times with chloroform. and the combined organic layers were dried (Mo950)) and evaporated in vacuo Purification by flash chromatography using a 3-2095 gradient mixture of ammonia-saturated methanol/chloroform gave the target product.

Solvents are removed in vacuo and displaced with two portions of ether. 154 mg (5690) of a white solid product are obtained. MS with electrospray 274 |MNI". b Example 33 - 4-Chlorospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-b|pyridines and 4'- chlorospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-s|Ipyridines and Complex 4-chlorospiro|1-azabicyclo|2.2.2)octane-3, 2'-(3'H)-furo|2,3-VIpyridine|-borane and complex

Ge") 20 4-chlorospiro|1-azabicyclo(2.2.2)octane-3,2'-(3'H)-furo|2,3-s|Ipyridine-borane is obtained from 2,3bg (7.84 mmol ) complex of 3-(2,4-dichloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo|2.2.2|octane-M-borane and 319 mg (7.97 mmol)

T» of sodium hydride in dimethylformamide as in preparation 2. This mixture is treated with aqueous hydrobromic acid in acetone to give, after flash chromatography on neutral silica gel using a mixture of 98:2 ammonia-saturated chloroform/ethanol, 559 mg of 4-chlorospiro|1-azabicyclo /2.2.2) octane-3,2'-(3'H)-furo|2,3-BI|Ipyridine), m.p. 109-110" (ethyl simple

HF) ether) and 46 mg of 4"-chlorospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-s|Ipyridine), m.p. 113-115760 .

Example 34 o Spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-c|Ipyridine 4-Chlorospiro|1-azabicyclo|2.2.2)octane-3 ,2'-(3'H)-furo2,3-c|Ipyridine) (125mg or 5.mmol) from example 33 60 is dissolved in 5O0ml of anhydrous methanol and 25mg of 1095 palladium on charcoal is added. The vessel is placed on the apparatus

Steam in a hydrogen atmosphere and shake for 2.5 hours. Ra/C is removed by filtration and washed with methanol. The solvent is removed in vacuo and the residue is dissolved in chloroform and methanol and transferred to a test tube. The solvent is removed in vacuo and displaced with two portions of ether. After drying in a high vacuum, 112 mg of an off-white powder (10495 with residual solvent) is obtained. MS with bo electrospraying 217|MNI".

Example 35 4-Methoxyspiro|1-azabicyclo|2.2.2)octane-3 2'-(3'H)-furo|2,3-B|pyridine| Sodium hydride (241 mg, 6.0 mmol) was added to a solution of 7 mg (0.30 mmol) of 4-chlorospiro|1-azabicyclo(2.2.2)octane-3,2'-(3'H)-furo|2,3 -B|pyridine)|. In 25 ml of ice-cooled methanol in a nitrogen atmosphere. The resulting solution is heated to reflux and stirred for 4 days, then cooled to room temperature, poured into ZOml of water and extracted with chloroform (ZxZOml). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue flash chromatographed on neutral silica gel using a 9:11 mixture of ammonia-saturated chloroform/methanol to give 5 mg (67905) of the title compound as a white solid product: MS with electrospray (IP/2, relative intensity) 247 |MNI.

Example 36 4"-Phenylthiospiro|1-azabicyclo(|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridine Sodium hydride (151 mg, 3.77 mmol) is added to a solution of 97 mg (0.387 mmol) 75 4-chlorospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo2,3-b|Ipyridine)Y, O4Oml (3.91 mmol) of thiophenol and 1Oml of methanol in 15 ml of dioxane under a nitrogen atmosphere.The reaction mixture is refluxed for 4 days, cooled to room temperature, diluted with 30 ml of water and extracted with chloroform (30 ml).

The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue flash chromatographed on neutral silica gel using a mixture of 98:22 ammonia-saturated chloroform//methanol to give 5 mg (52905) of the title compound as a colorless oil: MS with electrospraying (t/2, relative intensity) 325 (IMNI").

Example 37 4-(M-2-Aminoethyl)aminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine

A solution of 74 mg (0.295 mmol) of 4'-chlorospiro|1-azabicyclo(|2.2.2)|octane-3,2'-(3'H)-furo|2,3-B|Ipyridine)| in iOml. SI ethylenediamine is heated to reflux under a nitrogen atmosphere and stirred for 4 days. After cooling to room temperature, the solvent is removed in vacuo. The residue is dissolved in 20 ml of saturated aqueous sodium carbonate and extracted with chloroform (3x25 ml). The combined organic extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a dark oil, ZOmg (100965): electrospray MS (tp/7, relative intensity) 275 "I zo "(MNI"U (Se)

Example 38 4-(4-M-Methylpiperazin-1-yl)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines (2)

A solution of 97 mg (0.387 mmol) of 4"-chlorospiro|1-azabicyclo(|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridine| in Tml "-- 1- methylpiperazine is heated to reflux under a nitrogen atmosphere and stirred for 18 hours. After cooling to room temperature, dilute with 40 ml of water, make the base with 2 ml of saturated aqueous sodium carbonate and extract with chloroform (3x25 ml). The combined organic extract dried over anhydrous magnesium sulfate, concentrated in vacuo and flash chromatographed on neutral silica gel using a 4:1 mixture of ammonia-saturated chloroform/methanol to give 59 mg (4895) of the title compound as an amber oil: MS with electrospray (t/ 7, relative intensity) 315

IMNI". - c Example 39 "» 4-(Phenylmethyl)aminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-b|pyridine) " Solution 97mg (0.387 mmol) 4"-chlorospiro|1-azabicyclo(|2.2.2)octane-3,2-(3'H)-furo|2,3-B|pyridine| in Bml of benzylamine is heated to reflux under a nitrogen atmosphere and stirred for 18 hours. After cooling to room temperature, dilute 40 ml of water, make the main 2 ml of saturated

Add aqueous sodium carbonate and extract with chloroform (3x25ml). The combined organic extract is dried over anhydrous magnesium sulfate, concentrated in vacuo and flash chromatographed on neutral silica gel using a mixture of 9:11 ammonia-saturated chloroform/methanol to give 42 mg (3495) of the title compound as white of solid product: MS with electrospray (IP/7, relative intensity) 322 ((МНИ1). (He) 50 Example 40

I» 4-(Methylamino)spiro|1-azabicyclo|2.2.2octane-3,2'-(3'H)-furo|2,3-B|pyridine| A solution of 15 mg (0.60 mmol) of 4-chlorospiro|1-azabicyclo(|2.2.2)octane-3,2-(3'H)-furo|2,3-B|pyridine) in 2 bBml of 4095 aqueous methylamine is heated to 1757C in a steel autoclave for 18 hours, then cooled to room temperature and concentrated in a vacuum. The residue is dissolved in 1Oml of ethanol, which contains 04ml of concentrated 99% hydrochloric acid, and the solution is left to stand overnight. After filtering, the solution is concentrated in

HF) under vacuum and the residue crystallized from isopropanol, obtaining 147 mg of the title compound as a white solid product: MS with electrospray (n/2, relative intensity) 246 (MNI).

Example 41 in Spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridine-7'-oxide

A solution of spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-bB|Ipyridine| (2.88g, 13.3 mmol) and aqueous hydrogen peroxide (3095, 5ml) in acetic acid (20ml) are heated at reflux.

After 16 hours. and 24 hours additional portions of hydrogen peroxide are added and heating is continued for a total of 48 hours. The solution is then evaporated, then the residue is redissolved in ethanol (40 ml), which was saturated with sulfur dioxide. After 4 hours the solution is evaporated and the residue is purified by HPLC on silica gel using as eluent a gradient of 0-5095 solvent mixture (/M solution of ammonia in methanol (2590)/methanol (2595)/chloroform (5095)) and chloroform. The title compound (934 mg, 4.0 mmol, 3095) is a solid product: MS OSI 233 (MNI").

Example 42

Spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-BIpyridine-6'-carbonitrile

A solution of spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridine-7"-oxide) (95 mg, 0.41 mmol) is dissolved in acetonitrile (2 mL). Triethylamine (0.12 mL, 87 mg, 0.86 mmol) was added followed by trimethylsilylcyanide (0.2 mL, 149 mg, 1.5 mmol). The solution was stirred at room temperature overnight, then heated to reflux. Approx. over water, additional trimethylsilylcyanide (0.2 mL) was added. After heating at reflux overnight, the solution was allowed to cool. 70% excess methanol was added and the solution was kept at room temperature for 4 h, then evaporated. The residue was purified by HPLC on silica gel , using a 0-2595 gradient of solvent mixture (7M ammonia in methanol (2590)/methanol (2590)/chloroform (50965)) and chloroform as eluent. The title compound (5Omg, 0.21 mmol, 51906) is a solid : MS with electrospray 242 (MNI).

Example 43 6'i-Chlorospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridine|. A solution of spiro|1-azabicyclo(2.2.2)octane-3,2-(3'H)-furo|2,3-ypyridine-7-oxide| (98 mg, 0.42 mmol) in phosphorus oxychloride (2 ml) is heated at reflux for 2 hours. The solution is evaporated, the residue is partitioned between aqueous potassium carbonate and chloroform, then the organic layer is dried (magnesium sulfate), filtered and evaporated. The residue is purified by HPLC on silica gel, using a 0-2590 gradient mixture of solvents (7M solution of ammonia in methanol (2596)/methanol (2596)chloroform (5095)) and chloroform as eluent.

The title compound (2bmg, 0.10 mmol, 2595) is a solid: electrospray MS of 251 (IMNI" with Z5Cl) and 253 (IMNI" with Z/CI).

Example 44 6'-Fluorospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-VIpyridines (a) Complex 6'-fluorospiro|1-azabicyclo|2.2 .2) octane-3,2'-(3'H)-furo|2,3-b|pyridine|-M-borane o

A solution of phenyllithium (1.8M in cyclohexane, 13.5 mL) was added to THF (15 mL) under an argon atmosphere. Diisopropylamine (0.5 ml) is added and the solution is cooled to -78"C (dry ice/acetone bath temperature). 2,6-difluoropyridine (1.23 ml, 1.56 g, 13.6 mmol), then a solution of the complex spiro|1-azabicyclo|2.2.2|octane-3,2'-oxirane|i-M-borane (76b5mg, 5.mmol) in L tetrahydrofuran is added dropwise. The solution is stirred at -78"C for an hour. and the specified cooling bath is then replaced by dry lidacetonitrile in the bath. The solution is then stirred overnight, heated to room temperature. (at)

Saturated aqueous sodium bicarbonate is added and the solution is then extracted with chloroform. The extract is then dried (M950), filtered and evaporated. The residue is dissolved in DMF (20 ml) and then added to a suspension of hexane-washed sodium hydride (6095 mixture with mineral oil, 507 mg, 12.7 mmol) in DMF (20 ml), which (Ce) is stirred at 0"C. The solution is stirred overnight , warmed to room temperature. Saturated aqueous sodium bicarbonate was added to the solution and then extracted with chloroform. The extract was then dried (M95O0,), filtered and evaporated, and the residue was purified by HPLC using a gradient of 5-5095 ethyl acetate and " hexane to give the subtitled compound (102 mg, 895, 0.41 mmol): MS with electrospray (tp/27) 247

IM-NO". - c (6) 6-Fluorospiro|1-azabicyclo(2.2.2|octane-3,2'-(3'H)-furo|2,3-ypyridine Complex "» 6'-fluorospiro| 1-azabicyclo|2.2.2)octane-3,2-(3'H)-furo|2,3-5Ipyridine|I-M-borane (98 mg, 0.40 mmol) is dissolved in acetone (ml). 4895 Aqueous hydrobromic acid (2ml) is diluted with water (2ml) and then added to the solution.

The resulting mixture is stirred at room temperature overnight. The solution is then evaporated and partitioned between aqueous sodium carbonate and chloroform. The organic extract is then dried (Mo50 4 ),

Me. filtered and evaporated, and the residue purified by HPLC using a 0-2595 gradient of a mixture of 1:1:2 7M solution of ammonia in methanol:methanol:chloroform and chloroform to give the title compound (3 mg, 0.168 mmol, 4395) as a solid product : MS with electrospray (Itp/2, relative intensity) 235 (MNI", ish 100). b 50 s"

Claims (32)

The formula of the invention 1. Spiroazabicyclic heterocyclic compounds of the formula о сн ШІІ where р 60 - х and -4 (СН)claim 65 where п is equal to 0 or 1, t is equal to 0 or 1, p is 0 or 1, X is oxygen or sulfur, M is CH, M or MO, M is oxygen, H" or P", A is M or C(B 2), C is M or C (B U, p is M or C(B7) provided that no more than one of A, c, and O is nitrogen, but at least one of U, A, C, and O is nitrogen or MO, B ! represents hydrogen or C.4-C.sub.4-alkyl, b, B.sub.3 and B" represent, independently, hydrogen, halogen, C.sub.41-C.sub.4-alkyl, C.sub.4-C.sub.4-alkenyl, C.sub.3-C.sub.-alkynyl, aryl, heteroaryl, OH, OC1-Cu-alkyl, SOV!, -CM, -MO", -MA?VE, -CEz or -05025CEz or B? and BZ or BZ and B, respectively, can together, with the participation of A and C or o and 0, respectively, form another six-membered aromatic t or heteroaromatic ring, which does not contain or contains up to two nitrogen atoms and is substituted by one or two of the following substituents: independently hydrogen, halogen, C.-4-Cu-alkyl, Co-C;-alkenyl, Co-C,-alkynyl, aryl, heteroaryl, OH, ОС1-Cu-alkyl, CO»B, -CM, -MO», -«ME?5, -SEz or -О50»SEz , 2?, and 5, independently, represent is hydrogen, C41-Cu-alkyl, C(IO)B", C(O)MNEAZ, C(OOVU, 802879) or can together represent (СН) С(СН»о)к, where О is О, 5 , MA"! or a bond equal to a number from 2 to 7, K equal to a number from 0 to 2, 2", 88, VU and KO are, independently, C4-Cu-alkyl, aryl or heteroaryl, or their enantiomer, He! or their pharmaceutically acceptable salts 2. Compound according to claim 1, where t is equal to 1. 3. Compound according to any of claims 1-2, where n equals 0. 4. Compound according to any of claims 1-3, where p is equal to 0. 5. The compound according to any of claims 1-4, where X represents oxygen. "AND 6. The compound according to any one of claims 1-5, where A is C(B2), C is C(BEZ) and O is C(B7). with 7. A compound according to any of claims 1-6, where t is 1, n is 0, p is 0, X is oxygen, A is C(B2), C is C(VU), O is C(B 7). me) 8. The compound according to claim 1, where the specified compound is: "- spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-in|pyridine, Zo 5' -bromospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo/|2,3-in|pyridine, ise) 5'-phenylspiro|1-azabicyclo|2.2.2) octane-3,2'-(3'H)-furo|2,3-in|pyridine, 5'-nitrospiro|1-azabicyclo|2.2.2|octane-3,2-(3'H)-furo| 2,3-VIpyridines, 1-chlorospiro|1-azabicyclo|2.2.2|octane-3,2-(3'H)-furo|2,3-VIpyridines, « 5-(phenylcarboxamido)spiro|1-azabicyclo| 2.2.2) octane-3,2'-(3'H)-furo|2,3-vI|pyridines, 5-(phenylaminocarbonylamino)spiro|1-azabicyclo|2.2.2|octane-3,2'-( 3'H)-furo|2,3-Vypyridines, Z c 5-(phenylsulfonylamido)spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-vYpyridines , "» 5'-aminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furoi|2,3-VIpyridines, " 5-M-methylaminospiro|1-azabicyclo|2.2. 2) octane-3,2'-(3'H)-furo|2,3-B|pyridines, 5-M,M-dimethylaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3 'H)-furo|2,3-B|pyridines, 5-M,M-diethylaminospiro|1-azabicyclo|2.2.2|octane-3,2-(3'H)-furo|2,3-VIpyridines, Me. 5-M-ethylaminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridine, - 5-M-benzylaminospiro|1-azabicyclo|2.2.2) octane-3,2'-(3'H)-furo|2,3-B|pyridines, 5-M-formamidospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)- furo|2,3-VI|pyridines, and 5-M-acetamidospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, Ge» 20 spiro |1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo/|2,3-VIisoquinolines, spiro|1-azabicyclo|2.2.2)octane-3,2'-(3 'H)-furo|2,3-B)quinolines, T» 5'-ethenylspiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furoi|2,3-VIpyridines, 5-(E)-(phenylethenyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, 5-(4-morpholino)spiro|1 -azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, 59 5-(1-azetidinyl)spiro|1-azabicyclo|2.2.2)octane-3, 2'-(3'H)-furo|2,3-B|pyridines, HF) 5'-(E)-(2-(4-pyridyl)ethenyl)spiro|1-azabicyclo|2.2.2)octane- 3,2-(3'H)-furo|2,3-in|pyridine, 5'-(E)-(2-(2-pyridyl)ethenyl)spiro|1-azabicyclo|2.2.2)octane-3 ,2-(3'H)-furo|2,3-in|pyridine, where 5-(2-trimethylsilylethynyl)spiro|1-azabicycle o|2.2.2)octane-3,2'-(3'H)-furo|2,3-vI|pyridines, 5'-ethynylspiro|1-azabicyclo|2.2.2)octane-3,2'-( 3'H)-furo|2,3-vI|pyridines, 6o 5'-(2-furyl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furoi|2 ... |1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-in|pyridine, spiro|1-azabicyclo|2.2.2)octane-3,2'-( 3'H)-furo|2,3-in|pyridine-5'-carbonitrile, spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-in |pyridine-5'-carboxamides, because 5-M'-(3Z-chlorophenyl)ureidoaminospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B| pyridine, 5-M'-(2-nitrophenyl)ureidoaminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, 4'-chlorospiro|1-azabicyclo| 2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, 4-methoxyspiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)- furo|2,3-vI|pyridines, 4-phenylthiospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, 4-(M-2- aminoethyl)aminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridine, 4-phenylaminospiro|1-azabicyclo|2.2.2|octane-3,2 '-(3'H)-furo|2,3-VIpyridines, 4 -methylaminospiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, 4 '-(4-M-methylpiperazin-1-yl)spiro|1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-VIpyridines, 70 4'-chlorospiro| 1-azabicyclo|2.2.2|octane-3,2'-(3'H)-furo|2,3-c|pyridines, spiro|1-azabicyclo|2.2.2)octane-3,2'-(3 'H)-furo|2,3-c|pyridines, 6'-fluorospiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-B|pyridines, spiro|1-azabicyclo|2.2.2)octane-3,2'-(3'H)-furo|2,3-v|pyridine-6'-carbonitrile, 6'-chlorospiro|1-azabicyclo|2.2.2 )octane-3,2'-(3'H)-furo|2,3-B|pyridine, or an enantiomer or a pharmaceutically acceptable salt thereof. 9. The compound according to any of claims 1-7, where M is MO. 10. The compound according to claim 9, 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. 11. A compound according to any one of claims 1-10 for use in therapy. 12. A compound according to any one of claims 1-10 for the preparation of a medicinal product for the treatment or prevention of human diseases or conditions in which activation of the d7-nicotinic receptor is useful. 13. The compound according to any one of claims 1-10 for obtaining a medicinal product for the treatment or prevention of psychotic disorders or disorders of the type of reduced intellectual activity. 14. The compound of claim 13, wherein the condition or disorder is Alzheimer's disease, learning disorder, cognitive impairment, attention deficit disorder, memory loss, or attention deficit hyperactivity disorder. at 15. The compound of claim 13, wherein the disorder is a state of fear, schizophrenia, or mania or manic depression. 16. The compound according to claim 13, wherein the disorder is Parkinson's disease, Huntington's disease, Tourette's disease or neurodegenerative disorders in which there is a loss of cholinergic synapses. "AND 17. A compound according to any one of claims 1-10 for the preparation of a medicament for the treatment or prevention of a disorder of the normal circadian rhythm, a condition after smoking cessation, addiction to nicotine, including EE, addiction resulting from the action of products containing nicotine, pain and nonspecific ulcerative colitis. F 18. A pharmaceutical composition comprising a compound according to any one of claims 1-10 in admixture with an inert pharmaceutically acceptable diluent or carrier. -- 19. Pharmaceutical composition according to claim 18 for use in the treatment or prevention of human diseases or conditions in which activation of the 7-nicotinic receptor is beneficial. 20. Pharmaceutical composition according to claim 18 for use in the treatment or prevention of psychotic disorders or disorders of the type of reduced intellectual activity. " 21. Pharmaceutical composition according to claim 18 for use in the treatment or prevention of Alzheimer's disease, learning disability (deficit) disorder, cognitive impairment, attention disorder, memory loss, hyperactivity type disorder manifested in attention disorder, fear state , schizophrenia or mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's disease, "» neurodegenerative disorders in which there is a loss of cholinergic synapses, a disorder of the normal circadian rhythm, a state after smoking cessation, nicotine addiction, including addiction resulting from the action products containing nicotine, pain and non-specific ulcerative colitis. Ge) 22. A method of treatment or prevention of human diseases or conditions, in which the activation of the 7-nicotinic receptor is useful, in which a therapeutically effective amount of the compound according to any of claims 1-10 is administered. (Se) 23. A method of treatment or prevention of psychotic disorders or disorders of the type of reduced intellectual activity, in which a therapeutically effective amount of the compound according to any of claims 1-10 is administered. b 24. The method of claim 23, wherein the disorder is Alzheimer's disease, learning disability, cognitive impairment, attention deficit disorder, memory loss, or attention deficit hyperactivity disorder. 25. The method according to claim 23, where the disorder is Parkinson's disease, Huntington's disease, Tourette's disease or neurodegenerative disorders in which there is a loss of cholinergic synapses. 26. The method of claim 23, wherein the disorder is a state of fear, schizophrenia, or mania or manic depression. at 27. A method for the treatment or prevention of a disorder of the normal circadian rhythm, a state after cessation of smoking, nicotine addiction, pain and non-specific ulcerative colitis, in which a therapeutically effective amount of the compound according to any one of claims 1-10 is administered. 60 28. The method of obtaining the compound of formula I according to any one of claims 1-8, where Х is M, its enantiomer or a pharmaceutically acceptable salt, in which the removal of the borane complex in the compound of formula II using an acid in a suitable solvent or heating is carried out of the complex in an alcohol solvent b5 m uu sny o sn VN -- r z I r(ISN;) o "| interaction with dimethylaminosulfur trifluoride and, where desired or necessary, conversion of the resulting compound of formula I or its enantiomer or its acid addition salt into its t pharmaceutically acceptable acid addition salt or conversion of the resulting racemic mixture of the compound of formula I into its enantiomer. 29. The method of obtaining the compound of formula I! according to claim 1, where B is hydroxide and M is M, by rearrangement of the compound of the formula | according to p.i., where M is MO, using carbonic anhydride or Acids in a suitable solvent. 30. The method of obtaining the compound of the formula | according to claim 1, where B ! is chlorine and M is M by rearrangement of a compound of formula I according to claim 1, where X is MO, using a chlorinating source such as phosphorus oxychloride in a suitable solvent. 31. The method of obtaining the compound of the formula | according to claim 1, where B! is cyano and U is M, Ga by rearrangement of the compound of formula I according to claim 1, where M is MO, using a source of cyanide, such as trimethylsilylcyanide, in a suitable solvent. i9) 32. Intermediate spiroazabicyclic heterocyclic compounds of the formula М 1, p is equal to 0 or 1, X represents oxygen or sulfur, M represents oxygen, H" or P", " A represents M or C(B2), w c C represents M or C(B U, with » Or is M or C(B7) " provided that no more than one of A, C and O is nitrogen, B! is hydrogen or C.4-Cu-alkyl, F 45 2, BZ and B are, independently, hydrogen, halogen, C 1-C/-alkyl, Co-C;-alkenyl, Co-C,-alkynyl, aryl, heteroaryl, OH, OC.-Ci-alkyl, CO», -CM , -MO», -ME?VZU, -SEz, -О805SEz, or B? and KZ or VZ and B", - respectively, can together, with the participation of A and C or o and 0, respectively, form another six-membered aromatic so or a heteroaromatic ring that contains from zero to two nitrogen atoms and is substituted with one or two of the following substituents: independently, hydrogen, halogen, C--C;-alkyl, C--C;-alkenyl, C-C,-alkynyl, aryl , heteroaryl, OH, and (22) OS.-C, -alkyl, I» Co, -SM, -MO», -MA?VE, -SEz, -0О802СЕz, 2? and 5, independently, represent hydrogen, C41-Cu-alkyl, C(IO)B", C(O)MNEAZ, C(OOVU, 802879) or can together be (СН2)О(СНо)к; where C) represents itself O, 5, MA" or connection, | is equal to a number from 2 to 7, K is equal to a number from 0 to 2, IF) 2", 88, VU, VO and KE"! represent, independently, C4-C6-alkyl, aryl or heteroaryl, ime) or their enantiomer. 60 Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 12, 15.12.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5