EP0853621A1 - Novel substituted azacyclic or azabicyclic compounds - Google Patents

Novel substituted azacyclic or azabicyclic compounds

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Publication number
EP0853621A1
EP0853621A1 EP96931759A EP96931759A EP0853621A1 EP 0853621 A1 EP0853621 A1 EP 0853621A1 EP 96931759 A EP96931759 A EP 96931759A EP 96931759 A EP96931759 A EP 96931759A EP 0853621 A1 EP0853621 A1 EP 0853621A1
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EP
European Patent Office
Prior art keywords
compound
azabicyclo
anyone
compound according
pyridylmethylene
Prior art date
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Application number
EP96931759A
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German (de)
French (fr)
Inventor
Preben Houlberg Olesen
John Bondo Hansen
Holger C. Hansen
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Novo Nordisk AS
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Novo Nordisk AS
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Publication date
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Publication of EP0853621A1 publication Critical patent/EP0853621A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to heterocyclic compounds which are cholinergic ligands selective for neuronal nicotinic channel receptors, to methods for their preparation, to pharmaceutical compositions comprising them, and to their use in treating cognitive, neurological and mental disorders, such as dementia and anxiety, which are characterized by decreased cholinergic function.
  • the invention also relates to a method of treating Parkinson's disease by modulating the process of dopamine secretion, a method of treating or preventing withdrawal symptoms caused by cessation of chronic or long term use of tobacco products, as well as a method for treating obesity.
  • Nicotinic and muscarinic receptors are the two distinct types of choliner ⁇ gic receptors named after their selectivity for muscarine and nicotine, respectively.
  • the cholinergic system is the neurotransmitter system that best correlates with memory and cognitive functions.
  • SDAT a cholinergic hypothesis for senile dementia of the Alzheimer type
  • mAChR muscarinic acetylcholine receptors
  • nAChR nicotinic acetylcholine receptors
  • Parkinson's disease is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity.
  • nicotine may also have beneficial effects in PD.
  • Nicotine has also shown beneficial effects in Tourette's syndrome (Sanberg et al., Biomed. Phamacother., Vol. 43, pp. 1 9-23, (1 989)). Alleviation of negative psychotic symptoms, known as the hypofrontality syndrome in schizophrenia, by nicotinic agonists, have been suggested by data showing that nicotine stimulates dopamine release in the nucleus accumbens more potently than in stria ⁇ tum, (Rowell et al. J. Neurochem., Vol. 49, pp. 1449-1454, (1 987); Giorguieff-Chesselet et al., Life Sciences, Vol. 25, pp. 1257-1 262,
  • the present invention relates to novel substituted azacyclic or azabicyclic compounds of formula la, lb and Ic selected from the following:
  • x is 1 ,2,3,4 or 5; and n is 1 , 2 or 3; and m is 1 , 2 or 3; and p is 0, 1 or 2; and s is 0, 1 or 2; and t is 0, 1 or 2; and u is 0, 1 or 2; and
  • R is hydrogen or C ⁇ -alkyl; and G is selected among the following hetero- cycles
  • R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, -NO 2 , -CN, -OR 5 , -SR 5 , C L ⁇ -alkylC L ⁇ -polyfluoroalkyl, C 2 . 6 -alkenyl,
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sul ⁇ phate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 6_6, 2 ( 1 977) which are hereby incorporated by reference.
  • the compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
  • C 3 . 6 -cycloalkyl refers to a radical of a saturated cyclic hydrocarbon having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • C 2 . 6 -alkenyl refers to an unsaturated hydrocar ⁇ bon chain having from 2 to 6 carbon atoms and at least one double bond such as vinyl, 1 -propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n- hexenyl and the like.
  • Polyfluoro in "C L ⁇ -polyfluoroalkyl” means a C ⁇ -alkyl substituted with from 2 to 13 fluorine atoms such as -CF 3 , -CH 2 -CF 3 , -CH 2 -CH 2 -CF 3 and - CH 2 -CH 2 -CH 2 -CF 3 and the like.
  • C 2 . 6 -alkynyl refers to an unsaturated hydrocar ⁇ bon chain having from 2 to 6 carbon atoms and at least one triple bond such as -C ⁇ CH, -CH 2 -CH 2 -C ⁇ CH, -CH(CH 3 )-C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CH, -CH(CH 3 )C ⁇ H and the like.
  • C 2 . 6 -alkoxyalkyl as used herein means a group of 2 to 6 carbons inter ⁇ rupted by an O such as -CH 2 -0-CH 3 , -CH 2 -CH 2 -0-CH 3 , -CH 2 -0-CH 2 -CH 3 and the like.
  • C 2 . 6 -alkylthioalkyl means a group of 2 to 6 carbons interrupted by an S such as -CH 2 -S-CH 3 , -CH 2 -CH 2 -S-CH 3 , -CH 2 -S-CH 2 -CH 3 and the like.
  • C 2 . 6 -alkylaminoalkyl means a group of 2 to 6 carbons interrupted by an N such as -CH 2 -NH-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -NH-CH 2 -CH 3 and the like.
  • halogen means fluorine, chlorine, bromine and iodine.
  • R represents H or C ⁇ -alkyl.
  • a preferred value is 2, 3 or 4
  • n, m and p is preferably respectively 2, 1 and 0 or 2, 2 and 0 or 3, 1 and 0 and s
  • t and u is preferably re- spectively 1 , 1 and 0 or 1 , 2 and 0 or 1 , 2 and 1 .
  • Preferred compounds include:
  • the invention also relates to a method of preparing the above mentioned compounds of formula I. These methods comprise: a) reacting a compound of formula II, III or IV
  • R 5 , R 6 , R 7 , R 8 and R 9 independently are straight or branched C ⁇ -alkyl, to give com ⁇ pounds of the general formula la, lb or Ic;
  • R 10 , R 11 and R 12 independently are straight or branched C ⁇ -alky! and -A-B-C-D-E- have the meanings defined above, to give compounds of the general formula la, lb or Ic.
  • the pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of 3 H-methylcarbamylcholine ( 3 H-MCC) (Abood and Grassi, Biochem. Phar ⁇ macol., Vol. 35, pp. 41 99-4202, (1 986)).
  • 3 H-MCC 3 H-methylcarbamylcholine
  • 3 H-MCC labels the nicotinic receptors in the CNS.
  • the inhibitory effect on 3 H-MCC binding reflects the affinity for nicotinic acetylcholine receptors.
  • Fresh or frozen rat, brain tissue (hippocampus or cortex) was homoge- - io ⁇
  • assay buffer 50mM Tris-HCI, pH 7.4, 1 20 mM NaCI, 5 mM KCI, 2 mM CaCI 2 , 1 mM MgCI 2
  • Pellets were subsequently reconstituted in assay buffer and an appropri ⁇ ate amount of tissue sample was mixed in tubes with 3 H-methylcarba- mylcholine (NEN, NET-951 ; final concentration 2 nM) and test drug.
  • the tubes were incubated at 0 °C for 60 min. Unbound ligand was separated from bound ligand by vacuum filtration through GF/B filters presoaked in 0.5 % polyethylenimine.
  • IC 50 values of the test compounds were determined by nonlinear regression analyses (GraphPad InPlot).
  • the pharmacological properties of the compounds of the invention can also be illustrated by determining their capability to inhibit the specific binding of 3 H-Oxotremorine-M ( 3 H-Oxo). Birdsdall N.J.M., Hulme E.C., and Burgen A.S.V. (1 980). "The Character of Muscarinic Receptors in Different Regions of the Rat Brain” . Proc. Roy. Soc. London (Series B) 207, 1 .
  • 3 H-Oxo labels muscarinic receptor in the CNS (with a preference for agonist domains of the receptors).
  • Three different sites are labelled by 3 H- Oxo. These sites have affinity of 1 .8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.
  • the inhibitory effects of compounds on 3 H-Oxo binding reflects the affinity for muscarinic acetylcholine receptors.
  • Fresh cortex (0.1 - 1 g) from male Wistar rats (1 50-250 g) is homogenized for 5- 10 s in 1 0 ml 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 ml of buffer and the combined sus ⁇ pension centrifuged for 1 5 min. at 40,000 x g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2 x 1 0 ml of buffer and centrifuged for 10 min. at 40,000 x g.
  • the final pellet is homogenized in 20 mM Hepes pH: 7.4 ( 1 00 ml per g of original tissue) and used for binding assay. Aliquots of 0.5 ml is added 25 ul of test solution and 25 ul of 3 H-Oxotremorine (1 .0 nM, final concentra- tion) mixed and incubated for 30 min. at 25°C. Non-specific binding is determined in triplicate using arecoline ( 1 ug/ml, final concentration) as the test substance. After incubation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 ml of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.
  • Test substances are dissolved in 1 0 ml water (if necessary heated on a steam-bath for less than 5 min.) at a concentration of 2.2 mg/ml. 25-
  • IC 50 the concentration (nM) of the test substance which inhibits the specific binding of 3 H-Oxo by 50%).
  • IC 50 (applied test substance concentration) x(C x /C 0 -C x )nM
  • Table I illustrates the affinity of the compounds of the present invention for nicotinic and muscarinic receptors as determined by 3 H-MCC and 3 H- Oxo binding to rat cortical receptors.
  • the compounds show selective affinity for nicotinic receptors as compared to muscarinic receptors, i.e OXO/MCC > 1 .
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 1 00 mg, preferably from about 0.1 to about 100 mg, per day may be used.
  • a most preferable dosage is about 10 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the route of administration may be any route, which effectively trans ⁇ ports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intra ⁇ venous, intraurethral, intramuscular, topical, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • Typical compositions include a compound of formula la, lb or Ic or a phar ⁇ maceutically acceptable acid addition salt thereof, associated with a phar ⁇ maceutically acceptable carrier.
  • conventional techniques for the preparation of pharmaceutical compositions may be used.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be solid, semisolid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxyl- ated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteri- ously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds are dispensed in unit form comprising from about 1 to about 1 00 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • reaction mixture was stirred for 45 min., then cooled to -60 °C , and 1 - azabicyclo[2.2.1 ]heptan-3-one ( 0.85 g, 7.6 mmol dissolved in tetrahy- drofuran ( 1 0 ml) was added.
  • the reaction mixture was stirred at -60 °C for 1 .5 hours, then quenched with water (100 ml), and made alkaline with solid potassium carbonate. The water phase was extracted with ether (3x75 ml). The combined organic extracts were dried over magne ⁇ sium sulfate and evaporated.
  • reaction mixture was stirred for 45 min., then cooled to -60 °C , and 1 -benzyl-3-piperidone (2.3 g, 10.0 mmol ) dissolved in tetrahy- drofurane ( 1 0 ml) was added.
  • the reaction mixture was stirred at -60 °C for 1 .5 hours, then quenched with water (100 ml). The water phase was extracted with ether (3x75 ml). The combined organic extracts were dried over magnesiumsulfate and evaporated. The residue was purified by column chromatography on silica (eluent: ethylacetate).
  • the first frac ⁇ tions contained the (Z)-benzyl-3-(3-pyridylmethylene)piperidine isomer, which was isolated in 25 % (650 mg) yield.
  • the next fractions contained the (E)-benzyl-3-(3-pyridylmethylene)piperidine isomer, which was iso ⁇ lated in 23 % (600 mg ) yield.

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Abstract

The present invention relates to therapeutically active heterocyclic compounds, to methods for their preparation and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases in the central nervous system related to malfunctioning of the nicotinic cholinergic system.

Description

Novel Substituted Azacyclic or Azabicyclic Compounds
Field of the Invention
The present invention relates to heterocyclic compounds which are cholinergic ligands selective for neuronal nicotinic channel receptors, to methods for their preparation, to pharmaceutical compositions comprising them, and to their use in treating cognitive, neurological and mental disorders, such as dementia and anxiety, which are characterized by decreased cholinergic function. The invention also relates to a method of treating Parkinson's disease by modulating the process of dopamine secretion, a method of treating or preventing withdrawal symptoms caused by cessation of chronic or long term use of tobacco products, as well as a method for treating obesity.
Background of the Invention
Nicotinic and muscarinic receptors are the two distinct types of choliner¬ gic receptors named after their selectivity for muscarine and nicotine, respectively. The cholinergic system is the neurotransmitter system that best correlates with memory and cognitive functions. Traditionally, the cholinergic hypothesis for senile dementia of the Alzheimer type (SDAT) has focused on muscarinic acetylcholine receptors (mAChR), and only recently an interest in the role of the nicotinic acetylcholine receptors (nAChR) in SDAT has emerged. This interest was spurred by the rela- tively recent discovery that nAChR are not only located on the skeletal muscle but also in the brain.
It has been shown that the number of nAChR were decreased in SDAT patients (Nordberg et al. J. Neurosci. Res. Vol. 31 , pp. 103- 1 1 1 (1 992); Giacobini Advances in Experimental Medicine and Biology, Vol. 296, pp.9205-9295, ( 1 993); Schroeder et al., Neurobiol. of Aging, Vol. 1 2, pp. 259-262, ( 1 991 ); Whitehouse et al., Neurology, Vol. 38, pp. 720- 723, (1988); Flynn and Mash, J. Neurochem., Vol. 47, pp. 8702-8702, ( 1 993)). Similar deficiencies in choline acetyltransferase activity and acetylcholine synthesis suggest that presynaptic receptors on cholinergic nerve terminals are preferentially lost in SDAT (Nordberg, J. Reprod. Fert. Suppl., Vol 46, pp. 145-1 54, (1 993)). Therefore, it has been assumed that the loss of nAChR may correlate with age related onset of disorders of memory and cognitive functions, and that nicotinic replacement therapy may prove beneficial in SDAT. Indeed nicotine improved attention and memory in healthy humans (Warburton, Prog. Neuro. Psychopharma- col. Biol.. Psychiatry, Vol. 1 6, pp. 1 81 -1 91 , ( 1 992)) as well as in Alz¬ heimer's disease patients, (Jones et al. Psychopharmacology, Vol. 108, pp. 485-494, (1 992); Gitelman and Prohovnik, Neurobiol. of Aging, Vol. 1 3, pp. 31 3-31 8, ( 1 992); Newhouse et al., Psychopharmacology, Vol. 95, pp. 1 71 -1 75, ( 1 988); Sahakian et al., Br. J. Psychiatry, Vol.1 54, pp. 9004-904, (1 993)). Further the nicotinic antagonist mecamylamine has been shown to cause cognitive impairment in an age related way, (Newhouse et al., Neuropsychopharmacology, Vol 1 0, pp. 93-107, (1 994)).
Parkinson's disease (PD) is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity. There is evidence that nicotine may also have beneficial effects in PD. Studies show that smoking may protect against the development of PD, (Ishikawa and Mmiyatake, J. Neurol. Sci., Vol. 1 1 7, pp. 28-32, (1 993); Godwin-Austen et al., J. Neurol.. Neurosurg. Psychiat., Vol. 45, pp. 577-581 , (1 982); Reavill, in Nicotine psychopharmacology: Molecu¬ lar, cellular and behavioral aspects, pp. 307-340, Oxford University Press, (1 990)), and that chronic nicotine may protect against cell loss in the substantia nigra caused by lesioning (Janson and Moller, Neuro- science. Vol. 57, 931 -941 , ( 1 993)). Nicotine has also shown beneficial effects in Tourette's syndrome (Sanberg et al., Biomed. Phamacother., Vol. 43, pp. 1 9-23, (1 989)). Alleviation of negative psychotic symptoms, known as the hypofrontality syndrome in schizophrenia, by nicotinic agonists, have been suggested by data showing that nicotine stimulates dopamine release in the nucleus accumbens more potently than in stria¬ tum, (Rowell et al. J. Neurochem., Vol. 49, pp. 1449-1454, (1 987); Giorguieff-Chesselet et al., Life Sciences, Vol. 25, pp. 1257-1 262,
( 1 979)), by nicotinic reversal of inactivation of prefrontal neurons (Sven- son et al., In the Biology of Nicotine dependence., pp. 1 69-1 85, New York, (1 990)), and by the observation that nicotine will potentiate dopa¬ minergic effects in various behavioral models, (Reavill, in Nicotine psy- chopharmacology: Molecular, cellular and behavioral aspects, pp. 307- 340, Oxford University Press, (1 990); Rosecrans et al., Psychophar- macol. Commmun., Vol. 2, pp. 349-356, (1 976); Reavill and Stolerman, J. Psychopharmacol., Vol. 1 , pp. 264, (1 987)) .
In recent years there have been several studies on the effects of nicotine and food consumption and associated changes in body weight in rat and human. (Greenberg et al., Addictive behaviours, Vol. 7, pp. 317-331 , (1 982) and Greenberg et al., Psychopharmacology, Vol. 90, pp. 1 01 - 105, (1 984)). The appetite effects of nicotine have been suggested to be mediated via modulation of CCK peptides in the paraventricular hypotha- lamic nucleus (Fuxe et al., Acta Physiologica Scandinavica, Vol. 1 25, pp. 437-443, (1 985)).
Description of the invention
It is an object of the invention to provide novel heterocyclic compounds with affinity and selectivity for nicotinic cholinergic receptors, to methods for their preparation, to pharmaceutical compositions containing them, and to their use in treating Alzheimer's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis, obesity, other central nervous system and gastrointestinal disorders as well as severe pain.
The present invention relates to novel substituted azacyclic or azabicyclic compounds of formula la, lb and Ic selected from the following:
(la) (lb) (lc)
(la) (lb) (lc)
wherein x is 1 ,2,3,4 or 5; and n is 1 , 2 or 3; and m is 1 , 2 or 3; and p is 0, 1 or 2; and s is 0, 1 or 2; and t is 0, 1 or 2; and u is 0, 1 or 2; and
R is hydrogen or C^-alkyl; and G is selected among the following hetero- cycles
wherein R1 , R2, R3 and R4 independently are hydrogen, halogen, -NO2, -CN, -OR5, -SR5, CLβ-alkylCLβ-polyfluoroalkyl, C2.6-alkenyl,
C2.6-alkynyl, C3.6-cycloalkyl, C2.6-alkoxyalkyl, C2.6-alkylthioalkyl, C2.6- alkylaminoalkyl wherein R5 is hydrogen or C^-alky!; or a pharmaceutically acceptable salt thereof.
In the following there will also be used another form of presenting G:
wherein -A-B-C-D-E- is selected from -N = CfRVCfR2) = C(R3)-C(R4) = , -C(ϊV) = N-C(R2) = C(R3)-C(R4) = , -C(R1) = C(R2)-N = C(R3)-C(R4) = , -N = N-CfR1) = C(R2)-C(R3) = , -N = CfR'HM = C(R2)-C(R3) = , -N = CfR^-CfR2) = N-C(R3) = , -N = C(R1)-C(R2) = C(R3)-N = , -C R1) = N-N = C(R )-C(R3) = , -C(R1) = N-C(R2) = N-C(R3) = , -N = CfrVj-N = C(R2)-N = , -N = N-N = CfRVCfR2) = , -N = CfR'J-N = N-C(R2) = , -N = C(R1)-C(R2) = N-N = , -C(R1) = N-N = N-C(R2) = , -C(R1) = N-C(R2) = N-N = , -N = N-C(R1) -= N-N = , -C(R1) = N-N = N-N = , -N = C(R1)-N = N-N = .
Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sul¬ phate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 6_6, 2 ( 1 977) which are hereby incorporated by reference. The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
The term as used herein, alone or in combina¬ tion, refers to a straight or branched, saturated hydrocarbon chain having the indicated number of carbons such as for "C^-alky!" methyl, ethyl, n- propyl and isopropyl and for "CLβ-alkyl" methyl, ethyl, n-propyl, isopro- pyl, n-butyl, sec. butyl, isobutyl, tert. butyl, n-pentyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl and 2,2- dimethylpropyl and the like.
The term "C3.6-cycloalkyl" as used herein refers to a radical of a saturated cyclic hydrocarbon having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
The term "C2.6-alkenyl" as used herein refers to an unsaturated hydrocar¬ bon chain having from 2 to 6 carbon atoms and at least one double bond such as vinyl, 1 -propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n- hexenyl and the like.
"Polyfluoro" in "CLβ-polyfluoroalkyl" means a C^-alkyl substituted with from 2 to 13 fluorine atoms such as -CF3, -CH2-CF3, -CH2-CH2-CF3 and - CH2-CH2-CH2-CF3 and the like.
The term "C2.6-alkynyl" as used herein refers to an unsaturated hydrocar¬ bon chain having from 2 to 6 carbon atoms and at least one triple bond such as -C≡CH, -CH2-CH2-C≡CH, -CH(CH3)-C≤CH, -C≡CCH3, -CH2C≡CH, -CH(CH3)C≡H and the like.
"C2.6-alkoxyalkyl" as used herein means a group of 2 to 6 carbons inter¬ rupted by an O such as -CH2-0-CH3, -CH2-CH2-0-CH3, -CH2-0-CH2-CH3 and the like.
"C2.6-alkylthioalkyl" means a group of 2 to 6 carbons interrupted by an S such as -CH2-S-CH3, -CH2-CH2-S-CH3, -CH2-S-CH2-CH3 and the like.
"C2.6-alkylaminoalkyl" means a group of 2 to 6 carbons interrupted by an N such as -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-NH-CH2-CH3 and the like.
The term "halogen" means fluorine, chlorine, bromine and iodine.
In a preferred embodiment of the invention R represents H or C^-alkyl. For x, a preferred value is 2, 3 or 4, n, m and p is preferably respectively 2, 1 and 0 or 2, 2 and 0 or 3, 1 and 0 and s, t and u is preferably re- spectively 1 , 1 and 0 or 1 , 2 and 0 or 1 , 2 and 1 .
Preferred compounds include:
(Z)-3-(2-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane;
(Z)-3-(2-Pyrazinylmethylene)-1 -azabicyclo[2.2.2]octane; (Z)-3-(3-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane;
3-(4-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane;
3-(4-Pyrimidylmethylene)-1 -azabicyclo[2.2.2]octane;
(E)-3-(2-Pyrazinyl)methylene-1 -azabicyclo[2.2.2]octane;
(E)-3-(3-Pyπdylmethylene)-1-azabicyclo[2.2.2]octane; 3-(3-Pyridylmethylene)-1 -azabicyclo[2.2.1 ]heptane;
(E)-3-(3-Pyridylmethylene)piperidine;
(Z)-3-(3-Pyridylmethylene)-piperidine; or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of preparing the above mentioned compounds of formula I. These methods comprise: a) reacting a compound of formula II, III or IV
(ID (III) (IV)
wherein x, n, m, p, s, t, u and R have the meanings defined above with a phosphorus ylide of formula V or an alkyl phosphonate of formula VI
(V) (VI)
wherein -A-B-C-D-E- have the meanings defined above and R5, R6, R7, R8 and R9 independently are straight or branched C^-alkyl, to give com¬ pounds of the general formula la, lb or Ic;
b) reacting a compound of formula II, III or IV with a compound of formula VII (VII)
A-B-
Ll+_CH 2--<0 E-D
wherein -A-B-C-D-E- have the meanings defined above followed by dehydration, to give compounds of the general formula la, lb or Ic; or
c) reacting a compound of formula II, III or IV with a compound of for¬ mula VIII
wherein R10, R11 and R12 independently are straight or branched C^-alky! and -A-B-C-D-E- have the meanings defined above, to give compounds of the general formula la, lb or Ic.
The pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of 3H-methylcarbamylcholine (3H-MCC) (Abood and Grassi, Biochem. Phar¬ macol., Vol. 35, pp. 41 99-4202, (1 986)).
3H-MCC labels the nicotinic receptors in the CNS. The inhibitory effect on 3H-MCC binding reflects the affinity for nicotinic acetylcholine receptors.
Fresh or frozen rat, brain tissue (hippocampus or cortex) was homoge- - io ¬
nized in assay buffer (50mM Tris-HCI, pH 7.4, 1 20 mM NaCI, 5 mM KCI, 2 mM CaCI2, 1 mM MgCI2) and centrifuged for 10 min. at 40.000 x g. Pellets were subsequently reconstituted in assay buffer and an appropri¬ ate amount of tissue sample was mixed in tubes with 3H-methylcarba- mylcholine (NEN, NET-951 ; final concentration 2 nM) and test drug. The tubes were incubated at 0 °C for 60 min. Unbound ligand was separated from bound ligand by vacuum filtration through GF/B filters presoaked in 0.5 % polyethylenimine. Filters were washed three times with 5 ml wash buffer (50mM Tris-HCI, pH 7.4) and transferred to vials. 4 ml scintillation fluid was added and the radioactivity was measured by scintillation counting. Unspecific binding was measured with 10 μM nicotine.
The IC50 values of the test compounds were determined by nonlinear regression analyses (GraphPad InPlot).
Furthermore, the pharmacological properties of the compounds of the invention can also be illustrated by determining their capability to inhibit the specific binding of 3H-Oxotremorine-M (3H-Oxo). Birdsdall N.J.M., Hulme E.C., and Burgen A.S.V. (1 980). "The Character of Muscarinic Receptors in Different Regions of the Rat Brain" . Proc. Roy. Soc. London (Series B) 207, 1 .
3H-Oxo labels muscarinic receptor in the CNS (with a preference for agonist domains of the receptors). Three different sites are labelled by 3H- Oxo. These sites have affinity of 1 .8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.
The inhibitory effects of compounds on 3H-Oxo binding reflects the affinity for muscarinic acetylcholine receptors.
All preparations are performed at 0-4°C unless otherwise indicated. Fresh cortex (0.1 - 1 g) from male Wistar rats (1 50-250 g) is homogenized for 5- 10 s in 1 0 ml 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 ml of buffer and the combined sus¬ pension centrifuged for 1 5 min. at 40,000 x g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2 x 1 0 ml of buffer and centrifuged for 10 min. at 40,000 x g.
The final pellet is homogenized in 20 mM Hepes pH: 7.4 ( 1 00 ml per g of original tissue) and used for binding assay. Aliquots of 0.5 ml is added 25 ul of test solution and 25 ul of 3H-Oxotremorine (1 .0 nM, final concentra- tion) mixed and incubated for 30 min. at 25°C. Non-specific binding is determined in triplicate using arecoline ( 1 ug/ml, final concentration) as the test substance. After incubation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 ml of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.
Test substances are dissolved in 1 0 ml water (if necessary heated on a steam-bath for less than 5 min.) at a concentration of 2.2 mg/ml. 25-
75% inhibition of specific binding must be obtained before calculation of IC50. The test value will be given as IC50 (the concentration (nM) of the test substance which inhibits the specific binding of 3H-Oxo by 50%).
IC50 = (applied test substance concentration) x(Cx/C0-Cx)nM
where C0 is specific binding in control assays and Cx is the specific binding in the test assay. (The calculations assume normal mass-action kinetics).
Table I illustrates the affinity of the compounds of the present invention for nicotinic and muscarinic receptors as determined by 3H-MCC and 3H- Oxo binding to rat cortical receptors. The compounds, however, show selective affinity for nicotinic receptors as compared to muscarinic receptors, i.e OXO/MCC > 1 .
Table 1
Compoun d 3H-MCC 3H-Oxo Oxo/MCC ιc50 ιc50 Ratio nM nM
1 > 300 < 1000 -
2 180 720 4
3 4.2 890 212
The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 1 00 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 10 mg to about 70 mg per day. In choosing a regimen for patients suffering from diseases in the central nervous system caused by malfunctioning of the nicotinic cholin¬ ergic system it may frequently be necessary to begin with a dosage of from about 30 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
The route of administration may be any route, which effectively trans¬ ports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intra¬ venous, intraurethral, intramuscular, topical, intranasal, ophthalmic solution or an ointment, the oral route being preferred. Typical compositions include a compound of formula la, lb or Ic or a phar¬ maceutically acceptable acid addition salt thereof, associated with a phar¬ maceutically acceptable carrier. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semisolid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxyl- ated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteri- ously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
Generally, the compounds are dispensed in unit form comprising from about 1 to about 1 00 mg in a pharmaceutically acceptable carrier per unit dosage.
A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
Active compound 5.0 mg
Lactosum 67.8 mg Ph.Eur.
Avicel® 31 .4 mg
Amberlite® 1 .0 mg Magnesii stearas 0.25 mg Ph. Eur.
The invention will now be described in further detail with reference to the following examples:
EXAMPLE 1
(Z)-3-(2-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane dioxalate
A 2.5 M solution of n-butyllithium in hexane (3.4 ml, 8.5 mmol) was added over 5 min to a stirred solution of 2,2,6,6-tetramethylpiperidine (1 .1 9 g, 8.5 mmol) in 10 ml of dry tetrahydrofuran (THF) under nitrogen in a reaction vessel cooled in a dry ice/isopropyl alcohol bath at -75°C. The mixture was stirred for 10 min. To the resulting solution of lithium tetramethylpiperidine (LTMP), 2-trimethylsilylmethylpyridine (1 .4 g, 8.5 mmol) was added dropwise over 10 min. After stirring for 10 min a solution of 3-quinuclidinone (1 .8 g, 14 mmol) in 5 ml of THF was added over 1 5 min. Stirring was continued at -75°C for 1 h. Then the mixture was allowed to warm to room temperature with stirring during 1 /2 h, and 25 ml of water was added. The mixture was extracted with three 25 ml portions of diethylether. The extracts were combined and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 1 .55 g of a slowly crystallizing oil. The crystals were collected by filtration yielding 0.64 g (38%) of (Z)-3-(2-pyridylmethylene)-1 -azabicyclo[2.2.2]- octane. M.p. 76-78°C. 1 H NMR δ 8.65-8.55 (m, 1 H), 7.7-7.5 (m, 1 H), 7.2-7.0 (m, 2H), 6.35-6.2 (m, 1 H, C = CH-), 4.1 5-4.0 (m, 2H, N-CH2C = ), 3.1 -2.8 (, 4H, N-CH2-C), 2.6-2.45 (m, 1 H, methin),2.0-1 .7 (m, 4H, C-CH2-C).
To a solution of (Z)-3-(2-pyridylmethylene)-1 -azabicyclo[2.2.2]octane (0.5 g) in 4 ml of acetone was added with stirring at room temperature a solution of oxalic acid (0.7 g) in 3 ml of acetone. An additional 7 ml of acetone was added and the mixture was stirred for 1 h. The precipitate was filtered off and dried to give 1 .0 g ( 1 00%) of the title compound as a white powder. M.p. 1 62-1 64°C. (Compound 1 ).
EXAMPLE 2
The following compounds were prepared in the same manner as the Peterson reaction described in Example 1 . In cases where both (E) and (Z) isomers of the alkene were formed, the isomers could be separated by column chromatography on silica gel using a mixture of dichloromethane- /methanol/aqueous ammonia (80:20: 1 /2) as eluent.
(Z)-3-(2-Pyrazinyl)methylene-1 -azabicyclo[2.2.2]octane trioxalate starting from 2-trimethylsilylmethylpyrazine, LTMP, and 3-quinuclidinone. M.p. 147-1 52°C. (Compound 2).
(Z)-3-(3-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane dioxalate starting from 3-trimethylsilylmethylpyridine, lithium diisopropylamide (LDA), and 3-quinuclidinone. M.p. 1 97-200°C. (Compound 3).
3-(4-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane dioxalate starting from 4-trimethylsilylmethylpyridine, LTMP, and 3-quinuclidinone. M.p. 1 85- 1 88°C (melts partially at 142°C). (Compound 4).
3-(4-Pyrimidylmethylene)-1 -azabicyclo[2.2.2]octane oxalate starting from 4-trimethylsilylmethylpyrimidine, LTMP, and 3-quinuclidinone. M.p. 140- 145°C. (Compound 5).
(E)-3-(3-Pyridylmethylene)-1-azabicyclo[2.2.2]octane dioxalate, starting from 3-trimethylsilylmethylenepyridine, lithiumdiisopropylamine ( LDA) and 3- quinuclidinone. Compound 7. Mp 145-146 °C.
EXAMPLE 3
(E)-3-(2-Pyrazinyl)methylene-1 -azabicyclo[2.2.2]octane oxalate
To a solution of diisopropylamine (2.02 g, 20 mmol) in tetrahydrofuran (50 ml) was added butyllitium (2.5 M in hexanes, 8 ml, 20 mmol). The reaction mixture was stirred at 0°C for 30 min. then cooled to -78 °C. 2-Methylpyrazine ( 1 .88 g, 20 mmol ) in tetrahydrofuran (1 0 ml) was added and the reaction mixture was stirred for 1 hour at -78°C. Quinu- clidinone (3.75 g, 30 mmol) in tetrahydrofuran (1 0 ml) was added and the reaction mixture was stirred for another 1 hour at -78°C, then slowly heated to 0°C and stirred at this temperature for 0.5 hour. Triethylamine (4.5 g, 50 mmol) and thionyl chloride (8.0 g, 68 mmol) was added, and the reaction mixture was stirred for 0.5 hour. The reaction mixture was quenched with water (1 50 ml) and acidified with concentrated hydro¬ chloric acid. The water phase was extracted with ether (2 x 50 ml) then basified with solid potassium carbonate and extracted with ether (4 x 1 00 ml). The basic ether extracts were combined, dried over mag- nesiumsulphate and evaporated. The crude compound was crystallized as the oxalate salt from ethanol giving the title compound in 10 % yield. M.p. 149-1 50°C. (Compound 6). EXAMPLE 4
To a solution of diisopropylamine ( 1 .1 5 ml, 8.0 mmol ) in tetrahydrofuran (25 ml ) was added butyllitium (1 .6 M, 5 ml, 8 mmol). The mixture was stirred for 45 min at 0 °C, and 3-tertbutyldimethylsilylmethylenepyridine ( 1 .7 g, 8 mmol ) dissolved in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred for 45 min., then cooled to -60 °C , and 1 - azabicyclo[2.2.1 ]heptan-3-one ( 0.85 g, 7.6 mmol dissolved in tetrahy- drofuran ( 1 0 ml) was added. The reaction mixture was stirred at -60 °C for 1 .5 hours, then quenched with water (100 ml), and made alkaline with solid potassium carbonate. The water phase was extracted with ether (3x75 ml). The combined organic extracts were dried over magne¬ sium sulfate and evaporated. The residue was purified by column chro- matography on silica (eluent : methanol/ethylacetate/ammoniumhydroxide 25%: 1 :2:0.02). The product was isolated as a mixture of (Z) and (E) isomers in the relative proportion 2: 1 . The free base was crystallised as the oxalic acid salt from acetone in 45 % (770 mg) yield. Compound 8. Mp. 1 62-65 °C.
EXAMPLE 5
1 -Rpn7yl- -( -pγriHylmPthγlpnp)pippriHinp
To a solution of diisopropylamine ( 1 .5 ml, 1 0.0 mmol) in tetrahydrofuran (40 ml) was added butyllithium (1 .6 M, 6.3ml, 1 0 mmol). The mixture was stirred for 45 min at 0 °C, and 3-tertbutyldimethylsilylmethylene- pyridine (2.1 g, 1 0 mmol) dissolved in tetrahydrofuran ( 5 ml ) was added. The reaction mixture was stirred for 45 min., then cooled to -60 °C , and 1 -benzyl-3-piperidone (2.3 g, 10.0 mmol ) dissolved in tetrahy- drofurane ( 1 0 ml) was added. The reaction mixture was stirred at -60 °C for 1 .5 hours, then quenched with water (100 ml). The water phase was extracted with ether (3x75 ml). The combined organic extracts were dried over magnesiumsulfate and evaporated. The residue was purified by column chromatography on silica (eluent: ethylacetate). The first frac¬ tions contained the (Z)-benzyl-3-(3-pyridylmethylene)piperidine isomer, which was isolated in 25 % (650 mg) yield. The next fractions contained the (E)-benzyl-3-(3-pyridylmethylene)piperidine isomer, which was iso¬ lated in 23 % (600 mg ) yield.
EXAMPLE 6
(E)- -(3-PyririylmRthylRnf-*)pipRriHine
To a solution of (E)-benzyl-3-(3-pyridylmethylene)piperidine (600 mg, 2.3 mmol) in toluene ( 30 ml) was added 1 -chloroethyl chloroformate (0.38 ml, 3.5 mmol). The reaction mixture was heated at 100 °C for 1 hour, then evaporated. Methanol ( 25 ml) was added, and the reaction mixture was heated at reflux for 1 hour. The reaction mixture was evaporated and water ( 100 ml) was added. The water phase was made alkaline with solid potassium carbonate and extracted with ethylacetate (3 x 50 ml) . The combined organic extracts were dried over magnesiumsulfate and evaporated. The residue was purified by column chromatography on silica (eluent: methanol/ethylacetate/ammoniumhydroxide 25%: 1 :2:0.02). The free base was crystallised as the oxalic acid salt from acetone. Yield 90 mg ( 1 5 %). Compound 9. Mp 1 33-34 °C.
EXAMPLE 7
(7)- -(3-PyriHylmPthylpnp)pippriHinP Hihyrlrnr-- lnriH To a solution of (Z)-benzyl-3-(3-pyridylmethylene)piperidine (650 mg, 2.4 mmol) in toluen ( 30 ml) was added 1 -chloroethyl chloroformate (0.40 ml, 3.7 mmol). The reaction mixture was heated at 100 °C for 4 hours, then evaporated. Methanol ( 25 ml) was added, and the reaction mixture was heated at reflux for 1 hour. The reaction mixture was evaporated and water (100 ml) was added. The water phase was made alkaline with solid potassium carbonate and extracted with ethylacetate (3 x 50 ml ). The combined organic extracts were dried over magnesiumsulfate and evaporated. The residue was purified by column chromatography on silica ( eluent: methanol/ethylacetate/ammoniumhydroxide 25%: 1 :2:0.02) . The free base was crystallised as the hydrochloric acid salt from acetone. Yield 60 mg ( 1 4 %). Compound 10. Mp 21 8-21 °C.

Claims

L compound of formula la, lb or Ic
wherein x is 1 ,2,3,4 or 5; and n is 1 , 2 or 3; and m is 1 , 2 or 3; and p is 0, 1 or 2; and s is 0, 1 or 2; and t is 0, 1 or 2; and u is 0, 1 or 2; and
R is hydrogen or C^-alky!; and
G is selected among the following heterocycles
wherein R1 , R2, R3 and R4 independently are hydrogen, halogen, -N02, -CN, -OR5, -SR5, C2.6-alkenyl, C2.6-alkynyl, C3.6-cycloalkyl, C2.6-alkoxyalkyl, C2.6-alkylthioalkyl, C2.6- alkylaminoalkyl wherein R5 is hydrogen or C,.6-alkyl; or a pharmaceutically acceptable salt thereof.
A compound according to claim 1 wherein R is H or C1.3-alkyl.
3^ A compound according to anyone of the preceding claims wherein x is 2, 3 or 4. 4^ A compound according to anyone of the preceding claims wherein n, m and p is respectively 2, 1 and 0 or 2, 2 and 0 or 3, 1 and 0.
E . A compound according to anyone of the preceding claims wherein s, t and u is respectively 1 , 1 and 0 or 1 , 2 and 0 or 1 , 2 and 1 .
6^ A compound according to anyone of the preceding claims wherein
G is selected from the following heterocycles
Zi A compound according to claim 1 , wherein the compound is selected from the following:
(Z)-3-(2-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane; (Z)-3-(2-Pyrazinylmethylene)-1 -azabicyclo[2.2.2]octane;
(Z)-3-(3-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane;
3-(4-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane;
3-(4-Pyrimidylmethylene)-1 -azabicyclo[2.2.2]octane;
(E)-3-(2-Pyrazinyl)methylene-1 -azabicyclo[2.2.2]octane; (E)-3-(3-Pyridylmethylene)-1 -azabicyclo[2.2.2]octane;
3-(3-Pyridylmethylene)-1 -azabicyclo[2.2.1 Jheptane;
(E)-3-(3-Pyridylmethylene)piperidine;
(Z)-3-(3-Pyridylmethylene)-piperidine; or a pharmaceutically acceptable salt thereof.
8^ A method of preparing a compound according to claim 1 ,
CHARACTERIZED IN a) reacting a compound of formula II, ill or IV
(II) (IV)
wherein x, n, m, p, s, t, u and R have the meanings defined above with a phosphorus ylide of formula V or an alkyl phosphonate of formula VI
(V) (VI)
wherein -A-B-C-D-E- is selected from -N = C(R1)-C(R2) = C(R3)-C(R4) = , -C(H') = N-C(R2) = C(R3)-C(R4) = , -CfR1) = C(R2)-N = C(R3)-C(R4) = , -N = N-C(R1) = C(R )-C(R3) = , -N = CfR^-N = C(R )-C(R3) = , -N = C(R1)-C(R2) = N-C(R3) = , -N = C(R1)-C(R2) = C(R3)-N = , -C(R1) = N-N = C(R2)-C(R3) = , -C(R1) = N-C(R2) = N-C(R3) = , -N = C(R1)-N = C(R2)-N = , -N = N-N = C(R1)-C(R2) = , -N = C(R1)-N = N-C(R2) = , -N = CfRVCfR2) = N-N = , -C(R1) = N-N = N-C(R2) = , -C(R1) = N-C(R2) = N-N = , -N = N-C(R1) = N-N = , -C(R1) = N-N = N-N = , -N = C(R1)-N = N-N = and R5, R6, R7, R8 and R9 independently are straight or branched C,.6-alkyl, to give compounds of the general formula la, lb or Ic;
b) reacting a compound of formula II, III or IV with a compound of formula VII A-B
LΓ-CJ-V— Q'C (VII)
E-D
wherein -A-B-C-D-E- have the meanings defined above, followed by dehydration, to give compounds of the general formula la, lb or Ic; or
c) reacting a compound of formula II, III or IV with a compound of for¬ mula VIII
(VIII)
wherein R10, R1 1 and R12 independently are straight or branched C,.6-alkyl and -A-B-C-D-E- have the meanings defined above, to give compounds of the general formula la, lb or Ic. 9_, A pharmaceutical composition comprising as active component a compound according to anyone of claims 1 to 7 together with a pharma¬ ceutically acceptable carrier or diluent.
1 0. A pharmaceutical composition suitable for treating a disease in the central nervous system related to malfunctioning of the nicotinic cholinergic system comprising an effective amount of a compound according to anyone of claims 1 to 7 together with a pharmaceutically acceptable carrier or diluent.
1 1 . The pharmaceutical composition according to claim 9 or 1 0 in the form of an oral dosage unit or parenteral dosage unit.
1 2. The pharmaceutical composition according to claim 1 1 , wherein said dosage unit comprises from about 1 to about 1 00 mg of the com¬ pound according to anyone of claims 1 to 7.
1 3. A method of treating a central nervous system ailment related to malfunctioning of the nicotinic cholinergic system in a subject in need of such treatment comprising administering to said subject an effective amount of a compound according to anyone of claims 1 to 7.
14. A method of treating a central nervous system ailment related to malfunctioning of the nicotinic cholinergic system in a subject in need of such treatment comprising administering to said subject a pharmaceutical composition according to anyone of claims 9 to 1 2.
1 5. The use of a compound according to anyone of claims 1 to 7 for the preparation of a medicament for treatment of a disease in the central nervous system related to malfunctioning of the nicotinic cholinergic system. Our ref: 4532-WO,LaKe
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