NOVEL SUBSTITUTED AZACYCLIC COMPOUNDS

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 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, 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, (1 988); 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. 1449-1 454, (1 987); Giorguieff-Chesselet et al., Life Sciences, Vol. 25, pp. 1 257-1 262, (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. Psvchopharmacol., 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. 31 7-331 , ( 1 982) and Greenberg et al., Psychopharmacology, Vol. 90, pp. 101 - 1 05, (1 984)). The appetite effects of nicotine have been suggested to be mediated via modulation of CC 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 compounds with affinity and selectivity for nicotinic cholinergic receptors, to methods for their prepa¬ ration, to pharmaceutical compositions containing them, and to their use in treating Alzheimer's disease, Parkinson's disease, Tourette's syn¬ drome, ulcerative colitis, obesity, other central nervous system and gastrointestinal disorders as well as severe pain. The present invention relates to novel substituted azacyclic compounds of formula I selected from the following: wherein Z is oxygen or sulphur; and R 1 is hydrogen, C^-alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3 . 4 -cycloalkyl or benzyl; and R 2 and R 3 independently are hydrogen, C^-alkyl optionally substituted with one, two or three fluorine atoms or cyano, C 2 . 6 -alkenyl optionally substituted with one, two or three fluorine atoms, C 2 . 6 -alkynyl optionally substituted with one, two or three fluorine atoms, C 3 . 7 -cycloalkyl, phenyl or benzyl wherein each aromatic group is optionally substituted with halogen, C 1 . 4 -alkyl, -NO 2 , -CN, -CF 3 or -OR 6 wherein R 6 is hydrogen, C^- alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3 . 4 -cycloalkyl, or R 2 and R 3 form to¬ gether with the nitrogen atom a three, four, five, six or seven membered saturated or unsaturated heterocyclic ring; and R 4 is halogen, C^-alkyl optionally substituted by one, two or three fluorine atoms, C 2 . 6 -alkenyl optionally substituted by one, two or three fluorine atoms, C 2 . 6 -alkynyl optionally substituted by one, two or three fluorine atoms, C 3 . 7 -cycloalkyl, -OR 5 or -SR 5 wherein R 5 is C^-alkyl, C 2 . 6 - alkenyl or C 2 . 6 -alkynyl each of which is optionally substituted with one, two or three fluorine atoms; or a pharmaceutically acceptable salt thereof. 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, 636, 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. Alkyl, alkenyl and alkynyl as used herein mean straight or branched alkyl, alkenyl or alkynyl chains. In a preferred embodiment the compounds of the invention have the formula Ib wherein Z, R , R , R and R have the meanings defined above. 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 with a compound of formula wherein R 4 has the meaning defined above, which formed compound is reacted with hydroxylamine to give a compound of formula IV wherein R 4 has the meaning defined above, which formed compound is quaternized with R -Hal and subsequently reduced with sodium borohy¬ dride to form a compound of formula V wherein R 1 and R 4 have the meanings defined above, which formed compound can be stepwise alkylated with first R 2 -Hal and then R 3 -Hal to give a compound of formula VI wherein R , R , R and R have the meanings defined above; or b) a compound of formula IV wherein R 4 has the meaning defined above is stepwise alkylated with first R 2 -Hal and then R 3 -Hal to give a compound of formula VII wherein R 2 , R 3 and R 4 have the meanings defined above, which formed compound is quaternized with R 1 -Hal and subsequently reduced with sodium borohydride to give a compound of formula VI wherein R\ R 2 , R 3 and R 4 have the meanings defined above. 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 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¬ nized in assay buffer (50mM Tris-HCl, pH 7.4, 1 20 mM NaCl, 5 mM KCl, 2 mM CaCI 2 , 1 mM MgCI 2 ) 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 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. Filters were washed three times with 5 ml wash buffer (50mM Tris-HCl, 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 1 0 μM nicotine. The IC 50 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 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. 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 1 0 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 1 0 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 10 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 IC 50 . The test value will be given as 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 where C 0 is specific binding in control assays and C x 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 3 H-MCC and 3 H- 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 mpound 3 H-MCC 3 H-Oxo Oxo/MCC ιc 50 ιc 50 Ratio nM nM 3 230 4400 1 9 5 62 1400 23 7 40 5200 130 14 85 4000 47 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 100 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 1 0 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 I or a pharmaceuti¬ cally acceptable acid addition salt thereof, associated with a pharmaceuti¬ cally acceptable carrier. In making the compositions, conventional tech- niques 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, semi-solid, 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, polyhydroxyethoxylated 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, emuisifiers, salt for influencing osmotic pressure, buffers and/or coloring 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 100 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 α-(Dimethylamino)-α-(3-pyridyl)acetonitrile 1 -(3-Pyridyl)acetonitrile (5.9 g, 50 mmol) was dissolved in DMFDMA (1 0 ml) and stirred at 1 00°C for 0.5 hour. After cooling to room temperature diethyl ether was added and the title compound was filtered. Yield 8.2 g. 3-(5-Amino-4-isoxazolyl)pyridine To a solution of α-(dimethylamino)-α-(3-pyridyl)acetonitrile (5.1 9 g, 30 mmol) in acetic acid (40 ml) was added hydroxylamine hydrochloride (2.8 g, 40 mmol). The reaction mixture was stirred at 100°C for 1 hour, cooled to room temperature and concentrated in vacuo. Water ( 50 ml ) was added and the reaction mixture neutralized with solid potassium car- bonate. The precipitated compound was filtered washed with water and dried giving the title compound in 4.2 g yield. 3-(5-Amino-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 -methylpyridine oxalate To a solution of 3-(5-amino-4-isoxazolyl)pyridine (1 .0 g, 6.25 mmol) in acetone (25 ml) was added iodomethane (2 ml). The reaction mixture was stirred ovemight at room temperature, then evaporated in vacuo. The solid compound was dissolved in methanol (30 ml) and reduced by adding sodium borohydride (0.5 g, 1 3.5 mmol) in small portions. The reaction mixture was concentrated in vacuo and water (40 ml) was added. The water phase was extracted with ether (4 x 30 ml). The combined ether extracts were dried and evaporated. The crude compound was crystallized as the oxalate salt from acetone to give the title com¬ pound in 0.6 g yield. M.p. 1 38-1 39°C (Compound 1 ). In exactly the same manner the following compounds were prepared: 3-(5-amino-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 -ethylpyridine oxalate, star¬ ting from 3-(5-amino-4-isoxazolyl)pyridine and iodoethane (Compound 1 9). Mp. 1 1 2-1 1 3°C; 3-(5-amino-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 - benzylpyridine oxalate, starting from 3-(5-amino-4-isoxazolyl)pyridine and benzylbromide (Compound 20). Mp. 1 30-1 31 °C 3-(5-Dimethylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate and 3-(5-methylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methyl¬ pyridine oxalate To a solution of 3-(5-amino-4-isoxazolyl)pyridine (1 .6 g, 1 0 mmol) in DMF (20 ml) was added powdered potassium hydroxide (1 .0 g). The reaction mixture was stirred at room temperature for 5 min. and iodome¬ thane (1 .5 g, 1 2 mmol) was added. The reaction mixture was stirred for 5 min. at room temperature and water was added. The water phase was extracted with ether (3 x 50 ml). The combined extracts were dried and evaporated in vacuo. The residue was dissolved in acetone (30 ml) and iodomethane (2 ml, 32 mmol) was added. After stirring overnight the reaction mixture was concentrated jn vacuo. The residue was dissolved in methanol (30 ml) and reduced by adding sodium borohydride (720 mg, 20 mmol) in small portions at 0°C. The mixture was evaporated and water (50 ml) was added. The water phase was extracted with ethyl acetate (4 X 30 ml). The combined organic phases were dried and evapo- rated. The crude compound was purified by column chromatography (SiO 2 ; eluent: CH 2 CI 2 /MeOH : 9/1 ). The first fractions contained 3-(5- dimethylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine. The free base was crystallised as the oxalate salt giving the title compound in 500 mg yield. M.p. 106-1 07°C. (Compound 2). The later fractions contained 3-(5-methylamino-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 -metylpyri- dine. The free base was crystallized as the oxalate salt giving the title compound in 1 .0 g yield. M.p. 149-1 50°C. (Compound 3). In exactly the same manner the following compounds were prepared: 3-(5-Diethylamino-4-isoxazolyl)- 1 ,2, 5, 6-tetrahydro-1 -methylpyridine oxalate, M.p. 1 28-1 29°C, (Compound 4) and 3-(5-ethylamino-4-isoxazo- lyl)-1 , 2,5, 6-tetrahydro-1 -methylpyridine oxalate, M.p. 1 32-1 33°C, (Compound 5) both from 3-(5-amino-4-isoxazolyl)pyridine and iodo- ethane. 3-(5-Dipropylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate, M.p. 1 23-1 24°C, (Compound 6), and 3-(5-propylamino-4- isoxazolyl)-1 ,2,5,6-tetrahydro-1 -metylpyridine oxalate, M.p. 1 36-1 37°C, (Compound 7) both from 3-(5-amino-4-isoxazolyl)pyridine and iodopro- pane. 3-(5-Dibutylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate, M.p. 146-148°C, (Compound 8) from 3-(5-amino-4-isoxazolyl)- pyridine and iodobutane. 3-(5-Piperidinyl-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate, M.p. 138-140°C, (Compound 9) from 3-(5-amino-4-isoxazolyl)pyridine and 1 ,5-dibromopentane. EXAMPLE 4 3-(5-Amino-3-methyl-4-isoxazolyl)pyridine A solution of 3-pyridylacetonitrile (2.0 g, 17 mmol) in DMADMA (3 ml) was stirred at 100°C for 0.5 hour. The reaction mixture was evaporated lQ vacuo. The residue was dissolved in acetic acid (30 ml) and hydroxy¬ lamine hydrochloride (2.8 g, 40 mmol) was added. The reaction mixture was stirred at 100°C for 1 hour, cooled to room temperature and evapo¬ rated jn vacuo. Water (30 ml) was added to the residue and the reaction mixture was neutralized with solid potassium carbonate. The precipitated compound was filtered, washed with water and dried. Yield 1 .8 g. 3-(5-Amino-3-methyl-4-isoxazolyl)-1 ,2,5,6-tetrahydropyridine oxalate To a solution of 3-(5-amino-3-methyl-4-isoxazolyl)pyridine (0.9 g, 5 mmol) in a mixture of methanol (15 ml) and acetone (1 5 ml) was added iodomethane (2 ml, 32 mmol). The reaction mixture was stirred overnight at room temperature, then evaporated in vacuo. The solid material ob¬ tained was dissolved in methanol (40 ml) and reduced by adding sodium borohydride (0.5 g, 1 13.5 mmol) in small portions. The reaction mixture was concentrated in vacuo and water (40 ml) was added. The water phase was extracted with ethyl acetate (5 x 20 ml). The combined organic phases were dried and evaporated in vacuo. The crude compound was crystallized with oxalic acid from acetone in 800 mg yield (56 %). M.p. 1 89-1 90°C. (Compound 10). EXAMPLE 5 3-(5-Propylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate To a solution of 3-(5-amino-4-isoxazolyl)-1 ,2,5, 6-tetrahydro-1 -methylpy¬ ridine (1 .5 g, 8.3 mmol) in dimethylformamide (25 ml) was added pow- dered potassium hydroxide (1 .14 g, 20 mmol) . The reaction mixture was stirred at room temperature for 1 min. 1 -lodopropane (1 .41 g, 8.3 mmol) was added and the reaction mixture was stirred for 1 min. The reaction mixture was acidified with a 1 N hydrochloric acid solution. The water phase was extracted with ether (2 x 30 ml), then made alkaline with ammonium hydroxide (25% in water) and extracted with methylene chlo¬ ride (3 x 30 ml). The combined alkaline extracts were dried over magne¬ sium sulfate and evaporated. The residue was purified by column chro¬ matography (SiO 2 ; eluent: CH 2 CI 2 /MeOH : 9/1 ). The free base was crystallized with oxalic acid in acetone giving the title compound in 450 mg yield. (Compound 7). In exactly the same manner the following compounds were prepared: 3-(5-Methylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine and iodomethane. (Compound 3). 3-(5-Ethylamino-4-isoxazolyl)-1 ,2, 5, 6-tetrahydro-1 -methylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1 ,2, 5, 6-tetrahydro-1 -methylpyridine and iodoethane. (Compound 5). 3-(5-Butylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine and 1 - iodobutane. M.p. 125-126°C. (Compound 1 1 ). 3-(5-Pentylamino-4-isoxazolyl)- 1 ,2, 5, 6-tetrahydro-1 -methylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine and 1 -iodopentane. M.p. 99-100°C. (Compound 12). 3-(5-Hexylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine ox¬ alate from 3-(5-amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine and 1 -iodohexane. M.p. 92-93°C. (Compound 13). 3-(5-Benzylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine and benzylbromide. M.p. 1 10-1 12°C. (Compound 14). 3-(5-Cyanomethylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine and chloroacetonitrile. M.p. 149-150°C. (Compound 1 5). 3-(5-(2-Cyanoethyl)amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyri¬ dine oxalate from 3-(5-amino-4-isoxazolyl)-1 , 2,5, 6-tetrahydro-1 -methyl¬ pyridine and 2-bromopropionitrile. M.p. 142-143°C. (Compound 16). 3-(5-propylamino-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 -ethylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -ethylpyridine and iodopropane. M.p. 150-151 °C. (Compound 21 ). EXAMPLE 6 3-(5-Butylamino-3-methyl-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 -methylpyri- dine oxalate To a solution of 3-(5-amino-3-methyl-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 - methylpyridine (0.39 g, 2.0 mmol) in dimethylformamide (25 ml) was added powdered potassium hydroxide (0.3 g, 5 mmol) . The reaction mixture was stirred at room temperature for 1 min. 1 -lodobutane (0.25 ml, 2.1 mmol) was added and the reaction mixture was stirred for 1 min. The reaction mixture was acidified with a 1 N hydrochloric acid solution. The water phase was extracted with ether (2 x 30 ml), then made alkaline with ammonium hydroxide (25% in water) and extracted with methylene chloride (3 x 30 ml). The combined alkaline extracts were dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (SiO 2 ; eluent: CH 2 CI 2 /MeOH : 9/1 ). The free base was crystallized with oxalic acid in acetone giving the title com- pound in 60 mg yield. M.p. 1 1 6-1 1 7°C. (Compound 1 7). In exactly the same manner the following compound was made: 3-(5-Ethylamino-3-methyl-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 -methylpyri- dine oxalate from 3-(5-amino-3-methyl-4-isoxazolyl)-1 ,2,5,6-tetrahydro- 1 -methylpyridine and iodoethane. M.p. 1 28-1 29°C. (Compound 1 8).

Claims: CLAIMS j A compound of formula wherein Z is oxygen or sulphur; and R 1 is hydrogen, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3 . 4 -cycloalkyl or benzyl; and R 2 and R 3 independently are hydrogen, C^-alkyl optionally substituted with one, two or three fluorine atoms or cyano, C 2 . 6 -alkenyl optionally substituted with one, two or three fluorine atoms, C 2 . 6 -alkynyl optionally substituted with one, two or three fluorine atoms, C 3 . 7 -cycloalkyl, phenyl or benzyl wherein each aromatic group is optionally substituted with halogen, C 1 . 4 -alkyl, -NO 2 , -CN, -CF 3 or -OR 6 wherein R 6 is hydrogen, C^- alkyl, C 2 . 4 -alkenyl, C 2 . 4 -alkynyl or C 3 . 4 -cycloalkyl, or R 2 and R 3 form to¬ gether with the nitrogen atom a three, four, five, six or seven membered saturated or unsaturated heterocyclic ring; and R 4 is halogen, C^-alkyl optionally substituted by one, two or three fluorine atoms, C 2 . 6 -alkenyl optionally substituted by one, two or three fluorine atoms, C 2 . 6 -alkynyl optionally substituted by one, two or three fluorine atoms, C 3 . 7 -cycloalkyl, -OR 5 or -SR 5 wherein R 5 is C,. 6 -alkyl, C 2 . 6 - alkenyl or C 2 . 6 -alkynyl each of which is optionally substituted with one, two or three fluorine atoms; or a pharmaceutically acceptable salt thereof. -. A compound according to claim 1 having the formula Ib wherein Z, R\ R 2 , R 3 and R 4 have the meanings defined above; or a pharmaceutically acceptable salt thereof. 3_i A compound according to claim 1 selected from the following: 3-(5-Amino-4-isoxazolyl)-1 ,2,5, 6-tetrahydro-1 -methylpyridine, 3-(5-Dimethylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Methylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Diethylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Ethylamino-4-isoxazolyl)-1 ,2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Dipropylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Propylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Dibutylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Piperidinyl-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Amino-3-methyl-4-isoxazolyl)-1 ,2,5,6-tetrahydropyridine, 3-(5-Butylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Pentylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Hexylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Benzylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyridine, 3-(5-Cyanomethylamino-4-isoxazolyl)-1 , 2, 5, 6-tetrahydro-1 -methylpyri¬ dine, 3-(5-(2-Cyanoethyl)amino-4-isoxazolyl)-1 , 2,5, 6-tetrahydro-1 -methylpyri¬ dine, 3-(5-Butylamino-3-methyl-4-isoxazolyl)-1 , 2,5, 6-tetrahydro-1 -methylpyri¬ dine, 3-(5-Ethylamino-3-methyl-4-isoxazolyl)-1 ,2,5,6-tetrahydro-1 -methylpyri¬ dine; or a pharmaceutically acceptable salt thereof. ^ A method of preparing a compound according to claims 1 to 3, CHARACTERIZED IN a) reacting a compound of formula II with a compound of formula wherein R 4 has the meaning defined above, which formed compound is reacted with hydroxylamine to give a compound of formula IV wherein R 4 has the meaning defined above, which formed compound is quaternized with R 1 -Hal and subsequently reduced with sodium borohy¬ dride to form a compound of formula V wherein R 1 and R 4 have the meanings defined above, which formed compound can be stepwise alkylated with first R 2 -Hal and then R 3 -Hal to give a compound of formula VI wherein R , R , R and R have the meanings defined above; or b) a compound of formula IV wherein R 4 has the meaning defined above is stepwise alkylated with first R 2 -Hal and then R 3 -Hal to give a compound of formula VII wherein R 2 , R 3 and R 4 have the meanings defined above, which formed compound is quaternized with R 1 -Hal and subsequently reduced with sodium borohydride to give a compound of formula VI wherein R\ R 2 , R 3 and R 4 have the meanings defined above. 5. A pharmaceutical composition comprising as active component a compound according to any of claims claim 1 to 3 together with a pharmaceutically acceptable carrier or diluent. 6^. The pharmaceutical composition according to claim 5 in the form of an oral dosage unit or parenteral dosage unit. 7_i The pharmaceutical composition according to claim 6, wherein said dosage unit comprises from about 1 to about 100 mg of the com¬ pound according to any of claims 1 to 3. ∑ . A compound according to any of claims 1 to 3 for treating a central nervous system ailment related to malfunctioning of the nicotinic cholinergic system. JL. A compound according to any of claims 1 to 3 for treating Alz¬ heimer's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis, obesity, gastrointestinal disorders or severe pain, preferably obesity, or for treating or preventing withdrawal symptoms caused by cessation of chronic or long term use of tobacco products, preferably obesity. 1 0. The use of a compound according to any of claims 1 to 3 for the preparation of a medicament for treatment of a disease in the central nervous system related to malfunctioning of the nicotinic cholinergic system. 1 1 . The use of a compound according to any of claims 1 to 3 for the preparation of a medicament for treatment of Alzheimer's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis, obesity, gastrointestinal disorders or severe pain, preferably obesity, or for treat¬ ing or preventing withdrawal symptoms caused by cessation of chronic or long term use of tobacco products. 12. 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 any of claims 1 to 3. 13. A method of treating Alzheimer's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis, obesity, gastrointestinal disorders or severe pain, preferably obesity, in a subject in need of such treatment comprising administering to said subject an effective amount of a com- pound according to any of claims 1 to 3. 14. A method of treating or preventing withdrawal symptoms caused by cessation of chronic or long term use of tobacco products comprising administering to a subject in need thereof an effective amount of a compound according to any of claims 1 to 3.

Inventors: OLESEN PREBEN H, OLESEN, PREBEN, H.
Applicants: NOVONORDISK AS, OLESEN PREBEN H, NOVO NORDISK A/S, OLESEN, PREBEN, H.
Application year: 1996
Main classification: C07D413
IPC codes: A61K31, A61P25, C07D413, C07D417