MXPA00004396A - Azaring-ether derivatives and their use as nicotinic ach receptor modulators - Google Patents

Abstract

The present invention discloses compounds represented by general formula (I) any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof;wherein m is 1, 2 or 3;n is 1, 2 or 3;R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl;and R1 represents a monocyclic 5 to 6 membered heterocyclic group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino, nitro, -COOR3, -CONR2R3, -NH-CO2R2, NHCO-R2, -OCO-NR2R3;wherein R2 and R3 independently represents hydrogen or alkyl;aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro;-X-alkyl-Y-alkyl wherein X and Y independently represents O, S, NH, N-alkyl or Se;and alkyl is optionally substituted with alkoxy or thioalkoxy;-X-(alkyl)o-aryl- wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se;optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro;-X-(alkyl)o-5- or 6-membered heterocyclic monocyclic group wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se;optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro;a monocyclic 5 to 6 membered heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro;or R1 represents a bicyclic heterocyclic group, composed of a 5 to 6 membered monocyclic heterocyclic group fused to a benzene ring, and which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, alkoxy-alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino, nitro, aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro;and a monocyclic 5 to 6 membered heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro. The compounds of the invention are useful as nicotinic ACh receptor ligands.

Description

NITROGENED RING ETHER DERIVATIVES AND THEIR USE AS NICOTINIC ACH RECEIVER MODULATORS The present invention relates to novel pyridyl ether derivatives which are cholinergic ligands in nicotinic ACh receptors. The compounds of the invention are useful for the treatment of conditions or disorders or diseases involving the cholinergic system of the central nervous system, pain, inflammatory diseases, diseases caused by smooth muscle contractions and as auxiliaries to stop the excessive use of chemical substances.

BACKGROUND OF THE INVENTION The endogenous cholinergic neurotransmitter, acetylcholine, exerts its biological effect through two types of cholinergic receptors: muscarinic ACh receptors and nicotinic ACh receptors. Since it has been well established that muscarinic ACh receptors dominate quantitatively over nicotinic ACh receptors in the brain area important for memory and cognition, the vast majority of research aimed at the development of agents for the treatment of disorders related to Memory has been focused towards the synthesis of modulators of the muscarinic ACh receptor. However, recently there has been an interest in the development of nicotinic ACh receptor modulators. Several diseases are associated with the degeneration of the cholinergic system, for example senile dementia of the Alzheimer type, vascular dementia and cognitive deterioration due to the organic disease of brain damage directly related to alcoholism. Indeed, various CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency or a serotonergic deficiency. Alzheimer's disease is characterized by a profound loss of memory and cognitive functions caused by a severe depression of cholinergic neurons, ie neurons that release acetylcholine. A reduction in the number of nicotinic ACh receptors with the progression of Alzheimer's disease has also been observed. It is believed that the death of cortical neurons with the progression of Alzheimer's disease is due to a lack of stimulation of nicotinic ACh receptors. It is predicted that treatment with modulators of nicotinic ACh receptor of patients with Alzheimer's disease will not only improve the patients' memory but also act to keep these neurons alive. At present, it seems that smoking protects individuals against neurodegeneration and the compounds that act on this receptor could probably have a generally neuroprotective effect. However, the degeneration of the cholinergic system is not limited to individuals suffering from diseases, for example Alzheimer's disease, but it has also been observed in adults and in healthy elderly rats. Therefore, it is suggested that the cholinergic system is involved and is partially responsible for the memory disturbances observed in animals and in elderly humans. Therefore, the nicotine receptor modulator can be useful in the treatment of Alzheimer's disease, memory loss, memory dysfunction, dementia associated with AIDS, senile dementia or neurodegenerative disorders. Parkinson's disease seems to involve the degeneration of dopaminergic neurons. It has been observed that a symptom of the disease is the loss of nicotinic receptors associated with dopaminergic neurons and that it possibly interferes with the dopamine release process. Since sustained administration of nicotine increases the number of receptors present, the administration of nicotine receptor modulators could improve the symptoms of Parkinson's disease. Another condition or disorders or disease associated with deficiencies in the dopaminergic system are: drug addiction, depression, obesity and narcolepsy. Tourette syndrome is a neuropsychiatric disorder that involves a range of neurological and behavioral symptoms. It is believed that neurotransmitter dysfunction is involved, although the pathophysiology is still unknown and whether nicotine will be beneficial in the treatment of the disease (Devor et al., The Lancet, vol.8670 p.1046, 1989). Schizophrenia is a severe psychiatric illness. Neuroleptic compounds have been used in the treatment of the disease, and it is believed that the effect of the compounds is due to the interaction of these in the dopaminergic system. It is proposed that nicotine is effective in the treatment of schizophrenia (Adler et al., Biol Psychiatry, Vol. 32, pp. 607-616, 1992). It has been reported that nicotine has an effect on the release of the neurotransmitter in various systems. It has been reported that neurons release acetylcholine and dopamine after administration of nicotine (J. Neurochem, vol 43, 1593-1598, 1984) as well as the release of norepinephrine by Hall et. to the. (Biochem Pharmacol., Vol.21, 1829-1838, 1972). The release of serotonin by Hery et. al (Arch. Int. Farmacodyn, Ther. vol 296. pp. 91-97, 1977). The release of glutamate by Toth et. to the. (Neurochem, Res. Vol.17, p.265-271, 1992). It is believed that the serotonin system and dysfunction of the serotonergic system are involved in diseases or conditions or disorders such as: anxiety, depression, appetite disorders, obsessive-compulsive disorder, panic disorders, excessive use of chemical substances, alcoholism, pain, lack of memory and anxiety, pseudodementia, Ganser syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, excessive use of tobacco, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, difficulty of erection, anorexia nervosa, sleep disorders, autism, mutism or trichotillomania.

Nicotine improves the performance of concentration and tasks. Therefore, compounds that exhibit nicotine receptor modulating properties will likely be compounds useful in the treatment of learning deficiency, cognitive deficiency, attention deficiency, attention deficit hyperactivity disorder and dyslexia. It is recognized that the use of tobacco and especially cigarette smoking is a serious health problem. However, the nicotinic withdrawal symptoms associated with quitting smoking make it difficult to break this habit. Withdrawal symptoms include anger, anxiety, difficulty concentrating, restlessness, decreased heart rate and increased appetite and weight gain. Nicotine itself has been shown to ease withdrawal symptoms. Stopping the use of substances that cause addiction, for example opiates, benzodiazepines, ethanol, tobacco or nicotine, is in general a traumatic experience characterized by anxiety and frustration. It has been found that nicotine is effective in reducing irritability, anger, frustration and feelings of tension without causing a general response of depression, drowsiness or sedation and it is likely that compounds that have the same characteristics of nicotine have the same effects. Normally, mild to moderate pain can be treated with NSAIDs (non-steroidal anti-inflammatory drugs) although it is preferred to be used in opioids to treat moderate to severe pain. Opioids have some well-known side effects, including chemical dependence and potential for overuse as well as a depressive effect on the respiratory and gastrointestinal system. There is therefore a strong need for analgesic compounds that do not have these side effects and that can relieve mild, moderate and severe pain of an acute, chronic or recurrent nature as well as migraine pain and postoperative pain, extremity pain ghost. Epibatidine, a compound isolated from the skin of a poison frog, is a very potent analgesic with an approximate potency of 500 times that of morphine. The analgesic effect is not affected by naloxone, which is an indication of very little affinity towards the opiate receptors. Epibatidine is a nicotinic cholinergic receptor agonist and it is therefore very likely that compounds possessing this receptor modulator character also have a strong analgesic response. The compounds of the invention have proven to be useful for modulating smooth muscle contractions and therefore could be used in the treatment or prevention of condition or disorders or diseases inherent in smooth muscle contractions such as convulsive disorders, angina pectoris , premature birth, seizures, diarrhea, asthma, epilepsy, tardive dyskinesia and hyperkinesia. Furthermore, it is well known that nicotine has an effect on appetite and it is predicted that modulators of the nicotinic ACh receptor may be useful as appetite suppressants in the treatment of obesity and eating disorders. Cholinergic receptors play an important role in the functioning of muscles, organs and generally in the central nervous system. There are also complex interactions between cholinergic receptors and the function of the receptors of other neurotransmitters such as dopamine, serotonin and noradrenaline. It is likely that nicotine receptor modulating compounds may be effective in preventing or treating conditions or disorders or diseases such as: inflammation, inflammatory skin conditions, Chron's disease, inflammatory bowel disease, ulcerative colitis, diarrhea, neurodegeneration, peripheral neuropathy , lateral amyotrophic sclerosis, nociception, endocrine disorders, thyrotoxicosis, pheochromocytoma, hypertension, arrhythmias, mania, manic depression, Huntington's disease, delayed sleep cycle effect (jetlag). The compounds of the present invention are modulators of the nicotine receptor, and have the potential to exhibit nicotinic pharmacology, preferably without the side effects associated with nicotine itself. Additionally, compounds are expected to have the potential to act as neurotransmitter secretion enhancers and to suppress symptoms associated with low neurotransmitter activity.

OBJECTIVES OF THE INVENTION It is an object of the present invention to provide novel pyridyl ether derivatives which are useful for the treatment of a range of diseases and disorders characterized by decreased cholinergic function or which respond to the activity of nicotinic ACh receptor agonists. Another objective of the present invention is to provide novel pharmaceutical compositions containing these compounds, as well as methods for the preparation thereof and methods for the treatment thereof. Hereinafter, other objects will become apparent to a person skilled in the art.

BRIEF DESCRIPTION OF THE INVENTION The invention then, among other things, comprises the following, alone or in combination: A compound having the formula (I) any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein m is 1, 2 or 3; n is 1, 2 or 3; R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and R1 represents a 5-6 membered monocyclic heterocyclic group which may be substituted one or more times with substituents that are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3 , OCF3, CN, amino, nitro, -COOR3, -CONR2R3, -NH-CO2R2, NHCO-R2, -OCO-NR2R3; wherein R2 and R3 independently represent hydrogen or alkyl; aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; X-alkyl-Y-alkyl wherein X and Y independently represent O, S, NH, N-alkyl or Se; and alkyl is optionally substituted with alkoxy or thioalkoxy; -X- (alkyl) 0-aryl- wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; monocyclic heterocyclic group -X- (alkyl) 0-5- or 6-membered wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; a monocyclic 5- to 6-membered heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; or R1 represents a bicyclic heterocyclic group, composed of a 5- to 6-membered monocyclic heterocyclic group fused to a benzene ring, and which may be substituted one or more times with substituents that are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, alkoxy-alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino, nitro, aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; and a 5- to 6-membered monocyclic heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3CN, amino and nitro; Compounds as indicated above may contain isotopes of one or more of the atoms present. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of the above or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. The use of a compound as above for the manufacture of a medicament for the treatment or prevention of a condition or disorder or disease of a live animal, including a human, whose condition or disorder or disease responds to the activity of nicotinic ACh receptor modulators. A method for treating a disease in a living animal, including a human, whose disease responds to the activity of the nicotinic ACh receptor modulators, comprising the step of administering to such a living animal, including a human, in need thereof, a Therapeutically effective amount of a compound as the above.

DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment of the invention, the chemical compound of the formula (I) an acetidine, pyrrolidine, piperidine or a homopiperidine is the group bridging R and R1.

In another preferred embodiment of the invention R is hydrogen or C 1-4 alkyl; and R1 represents a pyridyl or a substituted pyridyl. In a more preferred embodiment, R1 is 3-pyridyl, 5-chloro-3-pyridyl, 2-chloro-3-pyridyl. In another preferred embodiment the chemical compound of the invention is a compound of the general formula (I) said compound being: (± 1-Methyl-3-oxy- (3-pyridyl) -pyrrolidine; (± 1-Methyl) -3-oxy (3-pyridyl) -azetidine; (± 1-Methyl-3-oxy (3-pyridyl) -piperidine; (±., 1-Methyl-3-oxy) (5-chloro-3-) pyridyl) -pyrrolidine; (±.? -1-Methyl-3-oxy (5-chloro-3-pyridyl) -piperidine; (±? -1- ethyl-3-oxy (2-chloro-3-) pyridyl) -piperidine; (±: -1-Methyl-4-oxy (3-pyridyl) -homopiperidine; (±: -1-Met.l-4-oxi (5-chloro-3-p Ridyl) -homopiperidine; (±:? -3-Oxy- (3-pyridyl) -pyrrolidine; (± 3-Oxy- (3-pyridyl) -azetidine; ? -3-Oxy- (3-pyridyl) -piperidine; (± - (5-chloro-3-pyridyl) -3-oxi-pyrrolidine; (±: - (5-chloro-3-pyr Dil) -3-oxy-piperidine; (±? - (2-chloro-3-pyridyl) -3-oxi-piperidine; (± 4-Oxi- (3-pyridyl) -homopiperi; d, or (+) - (5-chloro-3-pyridyl) -4-oxy-homopiperidine, any of its enantiomers or any of mixtures thereof, or a pharmaceutically salt acceptable of it.

Pharmaceutically acceptable addition salts The chemical compound of the invention can be provided in any suitable form for the proposed administration. Suitable forms include pharmaceutically acceptable salts (i.e., physiologically), and pre- or prodrug forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic organic and inorganic acid addition salts, such as acetic acid acetate acetate, aconitic acid derivative, ascorbic acid ascorbic acid derivative, benzene sulphonate benzene sulphonic acid derivative, benzoate derived from benzoic acid, cinnamic acid derived from cinnamic acid, citrate derived from citric acid, embonic acid derived from embonic acid, enanthate derived from enanthic acid, formate derived from formic acid, derived fumarate of fumaric acid, glutamate derived from glutamic acid, glycollate derived from glycolic acid, hydrochloride derived from hydrochloric acid, bromohydrate derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from acid malonic acid, mandelic acid derived from mandelic acid, methanesulfon ato derived from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, phthalate derived from italic acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, sulphate derived from sulfuric acid, tartrate derived from tartaric acid, toluene-p-sulfonate derived from acid p-toluene sulphonic, and the like. Said salts can be formed by methods known and described in the art. Other acids, such as oxalic acid, which can not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt. The metal salts of a chemical compound of the invention include alkali metal salts, such as the sodium salt of a chemical compound of the invention which contains a carboxy group. The chemical compound of the invention can be provided in solvated or unsolvated form together with pharmaceutically acceptable solvents, such as water, ethanol and the like. In general, solvated forms are considered equivalent to dissolved forms for the purpose of this invention.

Spherical isomers The chemical compounds of the present invention can exist in (+) and (-) forms as well as in racemic forms. The racemates of these isomers and the individual isomers themselves are within the scope of the present invention. Racemic forms can be resolved at optical antipodes through known methods and techniques. One way to separate the diastereomeric salts is by the use of an optically active acid, and the optically active amine compound is released by treatment with a base. Another method for resolving racemates in optical antipodes is based on chromatography in an optical active matrix. The racemic compounds of the present invention can therefore be resolved in their optical antipodes, for example, through fractional crystallization of d- or I- salts (tartrates, mandelics or camphor sulfonate), for example. The chemical compounds of the present invention can also be resolved by the formation of diastereomeric amides by reacting the chemical compounds of the present invention with an optically active activated carboxylic acid, such as that which is derived from (+) or (-) phenylalanine. , (+) or (-) phenylglycine, (+) or (-) cananic acid or by the formation of diastereomeric carbamates through the reaction of the chemical compound of the present invention with an optically active chloroformate or the like.

Additional methods for resolution of optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, & Wilen S in "Enantiomers, Racemates, and Resolutions". John Wiley and Sons, New York (1981). In addition, some of the chemical compounds of the invention contain double bonds and therefore can exist in two forms, cis- and trans- forms (Z- and E- form), depending on the placement of the substituents around the double bond. C = C-. A chemical compound of the present invention can therefore be cis- or trans- (form Z and E) or it can be a mixture thereof.

Definition of substitutents Halogen is fluoride, chloride, bromide or iodide. Alkyl means a straight chain or branched chain of one to eight carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl; cycloalkyl means cyclic alkyl of three to seven carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; "alkenyl" means a group of two to six carbon atoms, including at least one double bond, for example, but not limited to ethenyl, 1, 2- or 2,3-propenyl, 1, 2- or 2,3- or 3 , 4-butenyl. alkynyl means a group of two to six carbon atoms, including at least one triple bond, for example without being limited to ethynyl, 1, 2- or 2,3-propynyl, 1, 2- or 2,3- or 3,4 -butinyl. Cycloalkylalkyl means cycloalkyl as described and alkyl as already described, which means for example cyclopropylmethyl. Alkoxy is O-alkyl, wherein alkyl is as defined above. Cycloalkoxy is O-cycloalkyl, wherein cycloalkyl is as defined above. Alkenoxy is O-alkenyl, wherein alkenyl is as described above. Alkynoxy is O-alkynyl, wherein alkynyl is as described above; Thioalkoxy is S-alkyl, wherein alkyl is as defined above. Amino is NH2 or NH-alkyl or N- (alkyl) 2, wherein alkyl is as defined above. A heterocyclic group of 5 to 6 monocyclic elements, for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, soxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl , thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, siathiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,4-oxadiazol-3-yl, 1, 2,4-oxadiazol-5-yl, 1,4-thiadiazol-3-yl, 1,4-thiadiazol-5-yl, 1, 2,5-oxadiazol-3-yl, 1, 2,5-oxadiazol-4-yl, 1, 2,5-thiadiazol-3-yl, 1, 2,5-thiazol-4-yl, 1-imidazoloyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl and 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl. A bicyclic heterocyclic group consisting of a monocyclic heterocyclic group of 5 to 6 elements and a fused benzene ring means a heterocyclic group of 5 to 6 monocyclic elements as described, which is fused to a benzene ring, which includes, for example, -, 3-, 4-, 5-, 6-, 7-benzofu ramie, 1-, 2-, 4-, 5-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl , 2-, 3-, 4-, 5-, 6-, 7-, 8-quinoliniio and 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinilo. Aryl is an aromatic hydrocarbon, such as phenyl and naphthyl. Aralkyl means alkyl as described above and aryl as described, meaning for example benzyl, phenethyl. Isotopes means one or more atoms in the compound substituted with an isotope of atoms as they occur in nature and includes, but is not limited to, deuterium, tritium, 13 ^ C, 14 C-, 131? I, 125. 123. 18 5F; In addition, the compounds of this invention can exist in unsolvated forms, as well as in solvated forms, with pharmaceutically acceptable solvents, such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of this invention. Those skilled in the art will appreciate that the compounds of the present invention may contain several chiral centers and that said compounds exist in the form of isomers (ie, enantiomers). The invention includes said isomers and any mixture thereof including racemic mixtures. The racemic forms can be resolved into optical antipodes by known methods, for example, by separating diastereomeric salts thereof with an optically active acid, and by releasing the optically active amine compound by treatment with a base. Another method for resolving racemates in the optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can therefore be resolved in their optical antipodes, for example, by fractional crystallization of d- or I- salts (tartrates, mandelates, or camphor sulfonates). The compounds of the present invention can also be resolved by the formation of diastereomeric amides through the reaction of the compounds of the present invention with an optically active activated carboxylic acid, such as that which is derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) cananic acid or by the formation of diastereomeric carbamates through the reaction of the compounds of the present invention with an optically active chloroformate or the like. Additional methods for resolving known optical isomers may be employed, and will be apparent to those skilled in the art. These methods include those addressed by J. Jaques, A. Collet and S.

Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). The optically active compounds can also be prepared from optically active starting materials. The compounds of the invention can be prepared by any conventional method useful for the preparation of analogous compounds and as described in the examples below. The starting materials for the processes described in the present patent application are known or can be prepared by known methods from commercially available materials. A compound of the invention can be converted to another compound of the invention using conventional methods. The products of the reactions described herein are isolated by conventional means, such as extraction, crystallization, distillation, chromatography and the like.

Biology Nicotinic ACh receptors in the brain are pentameric structures composed of units different from those found in skeletal muscle. The existence of eight subunits a (a2-a9) and three subunits ß (ß2-ß4) in the mammalian brain has been described.

The predominant subtype with a high affinity for nicotine is composed of three a4 subunits and two β2 subunits. The affinity of the compounds of the invention for nicotinic ACh receptors has been investigated in three tests in terms of in vitro inhibition of 3 H-epibatidine binding, binding to 3 H-to-bungarotoxin and binding to 3 H-cytisine as described later: In vitro inhibition of 3H-cytisine binding The predominant subtype with high affinity for nicotine is composed of a4 and β2 subunits- The nAChR of this latter type can be selectively labeled by the nicotine modulator 3H-cytisine.

Tissue preparation The preparations were made at 0-4 ° C, unless otherwise indicated. The cerebral cortexes from male Wistar rats (150-250g) were homogenized for 20 seconds in 15 ml of Tris, HCl (50 mm, pH 7.4) containing 120 mM NaCl, 5 mM KCI, 1 mM MgCl2 and 2.5 mM of CaC using an Ultra-Turrax homogenizer. The homogenized material was centrifuged at 27,000 x g for 10 minutes. The supernatant was discarded and the pellet was resuspended in fresh buffer and centrifuged a second time. The final pellet was resuspended in fresh buffer solution (35 μg per gram of original tissue) and used for binding tests.

Test Aliquots of 500 μl of the homogenate were added to 25 μl of the test solution and 25 μl of 3 H-cytisine (final concentration 1 mM), mixed and incubated for 90 minutes at 2 ° C. The non-specific binding was determined using (-) - nicotine (final concentration 100 μM). After incubation, 5 ml of ice-cold buffer solution was added to the samples and poured directly into Whatman GF / C glass fiber filters under suction and immediately washed with 2 x 5 ml of ice-cold buffer solution. The amount of radioactivity in the filters was determined by conventional liquid scintillation technique. The specific binding is the total union minus the non-specific binding.

In vitro inhibition of Ha-bunqarotoxin binding in rat brain A-bungatoroxin is a peptide isolated from the venom of the viper Bungarus multicinctus of the Elapidae family (Mebs et al., Biochem. Biophys. Res. Commun., 44 (3 ), 711 (1971)), and has high affinity for neuronal and neuromuscular nicotinic receptors, where it acts as a potent antagonist. 3 H-a-bungarotoxin binds to an individual site in the rat brain with a unique distribution pattern in the rat brain (Clarke et al., J. Neurosa, 5, 1307-1315 (1985)). The 3H-a-bungarotoxin marks the nAChR formed by the form of the a7 subunit found in the brain and the isoform ai in the neuromuscular junction (Changeaux, Fidia Res. Found. Neurosci. Found, Lect. 4, 21-168 ( 1990) Functionally, the a7 homo-oligomer expressed in the oocytes has a greater calcium permeability than that of the neuromuscular receptors and, in some cases, greater than the NMDA channels (Seguela et al., J. Neurosci., 13, 596 -604 (1993).

Tissue preparation The preparations were made at 0-4 ° C, unless otherwise indicated. The cerebral cortexes from male Wistar rats (150-250 g) were homogenized for 10 seconds in 15 ml of 20 mM Hepes buffer solution containing 118 mM NaCl, 4.8 mM KCI, 1.2 mM MgSO4 and 2.5 mM CaCl2 ( pH 7.5) using an Ultra-Turrax homogenizer. The tissue suspension was centrifuged at 27,000 x g for 10 minutes. The supernatant was discarded and the pellet was washed twice by centrifugation at 27,000 xg for 10 minutes in 20 ml of fresh buffer, and the final pellet was resuspended in fresh buffer containing 0.01% BSA (35 ml per cell). gram of original tissue) and was used for the binding tests.

Test Aliquots of 500 μl of the homogenized material were added to 25 μl of the test solution and 25 μl of 3 H -bungarotoxin (final concentration 2 nM), mixed and incubated for 2 hours at 37 ° C. The non-specific binding was determined using (-) - nicotine (final concentration 1 mM). After incubation, 5 ml of ice cold Hepes buffer containing 0.05% PEI was added to the samples and poured directly into Whatman GF / C glass fiber filters (previously soaked in 0.1% PEI for at least 6 hours) under suction and immediately washed with 2 x 5 ml of ice buffer. The amount of radioactivity in the filters was determined by conventional liquid scintillation technique. The specific binding is the total union minus the non-specific binding.

In vitro inhibition of binding to 3H-epibatidine Epibatidine is an alkaloid that was first isolated from the skin of the Ecuadorean frog Epipedobates tricolor and found to have a high affinity towards neuronal nicotinic receptors, where it acts as a potent agonist. . 3 H-epibatidine binds to two sites in the rat brain, both of which have pharmacological profiles consistent with neuronal nicotinic receptors and a similar regional distribution in the brain (Hougling et al., Mol.Pharmacol., 48, 280- 287 (1995)). The high affinity binding site for 3H-epibatidine is surely the binding to the a4ß2 subtype of nicotinic receptors. The identity of the low affinity site is still unknown; it represents a second nicotinic receptor or a second site in the same receptor. The inability of a-bungarotoxin to compete for 3 H-epibatidine binding sites indicates that none of the sites measured represents the nicotinic receptor composed of a7 subunits.

Tissue preparation The preparations were made at 0-4 ° C, unless otherwise indicated. The posterior brain (+ cerebellum) from a male Wistar rat (150-250 g) was homogenized for 10-20 seconds in 20 ml of Tris, HCl (50 mM, pH 7.4) using an Ultra-Turrax homogenizer. The tissue suspension was centrifuged at 27,000 x g for 10 minutes. The supernatant was discarded and the pellet was washed three times by centrifugation at 27,000 xg for 10 minutes in 20 ml of fresh buffer, and the final pellet was resuspended in buffer solution (400 ml per gram of original tissue) and used for the binding tests.

Test Aliquots of 2.0 ml of homogenized material were added to 0.1 ml of the test solution and 0.1 ml of 3 H-epibatidine (final concentration 0.3 nM) was mixed and incubated for 60 minutes at room temperature. The non-specific binding was determined using (-) - nicotine (final concentration 30 μM). After incubation the mixtures were poured directly onto Whatman GF / C glass fiber filters (previously soaked in 0.1% PEI for at least 20 minutes) under suction and immediately washed with 2 x 5 ml of ice cold buffer. The amount of radioactivity in the filters was determined by conventional liquid scintillation technique. The specific binding is the total union minus the non-specific binding.

Compound 3 ?: 3H- *? Üx- cytisine epibatidine bungarotoxin Cl50 (μM) IC50 (μM) Cl50 (μM) 1-Methyl-3-oxy- (3-pyridyl) -pyrrolidine (1a) 0.10 0.70 16.0 1 - . 1 -Met-1-3-oxy- (3-pyridyl) -pyridine (3a) 0.19 0.72 19.0 Salt of 4-oxy- (3-pyridyl) -0.06 0.30 20.0 homopiperidinfumárico (7b) 3-Oxy- (3-pyridyl) -pyrrolidine (1 b) 0.07 0.41 > 30 The compounds of the present invention show a high degree of binding affinity, as well as selectivity for one or more of the receptor subtypes. Therefore, they have been shown to be useful as modulators of selective receptors of the nicotine receptor subtypes.

Pharmaceutical Compositions Although it is possible that, for use in therapy, a compound of the invention may be administered as the crude chemical substance, it is preferable to present the active ingredient as a pharmaceutical formulation. Therefore, the invention further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and / or prophylactic ingredients. The vehicle or vehicles must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not damaging the recipient thereof. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, vehicle or diluent, can therefore be placed in the form of pharmaceutical compositions and unit doses thereof and in such a form that they can be used as solids, such as tablets or filled capsules, liquids such as solutions, suspensions, emulsions, elixirs or capsules filled therewith, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous). Said pharmaceutical compositions and dosage unit forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and said unit dosage forms may contain any effective and adequate amount of the active ingredient provided at the dose scale. intended daily that will be employed. Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet are also representative and suitable unit dose forms. The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention. To prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component. In tablets, the active component is mixed with the vehicle having the necessary binding capacity in suitable proportions and is compacted in the desired shape and size. The powders and tablets preferably contain from 5 or 10 to about 70% of the active compound. The right vehicles are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a vehicle that provides a capsule in which the active component, with or without vehicles, is surrounded by a vehicle, which is therefore associated with the same. Similarly, sacks and pills are included. Tablets, powders, capsules, pills, sacks and pills can be used as solid forms suitable for oral administration. To prepare suppositories, a low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the active component is dispersed homogeneously therein, by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and subsequently solidified. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays which contain in addition to the active ingredient such vehicles which are known to be suitable in the art. Liquid form preparations include solutions, suspensions and emulsions, for example, solutions with water or water-propylene glycol. For example, liquid preparations in parenteral injection can be formulated as solutions in aqueous polyethylene glycol solution. The compounds according to the present invention can therefore be formulated for parenteral administration (for example, injection, for example bolus injection or continuous infusion) and can be presented in the form of unit doses in ampoules, prefilled syringes, low volume infusion or in multiple dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by solution lyophilization, for constitution with a suitable vehicle, eg, pyrogen-free sterilized water, before use. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing agents and thickeners, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other known suspending agents. Also included are solid form preparations which are intended to be converted, just before use, into liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, pH regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. For topical administration to the epidermis, the compounds according to the invention can be formulated as ointments, creams or lotions or as a transdermal patch. The ointments and creams can for example be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. The lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Formulations suitable for topical administration in the mouth include troches comprising active agents in a flavoring base, usually sucrose and acacia or tragacanth; the tablets comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprising the active ingredient in a suitable liquid vehicle.

The solutions or suspensions are applied directly to the nasal cavity through conventional means, for example with a dropper, pipette or sprinkler. The formulations can be provided in simple form or in multiple doses. In the latter case of a dropper or pipette, this can be achieved if the patient administers a predetermined appropriate volume of the solution or suspension. In the case of a sprinkler, it can be achieved, for example, by means of an atomizing spray pump with measurement. Administration to the respiratory tract can also be achieved by means of an aerosol formulation in which the active ingredient is supplied in a pressurized package with a suitable impeller such as chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or another suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of medication can be controlled by the provision of a metering valve. Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Conveniently the powder vehicle will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form for example in capsules or cartridges of, for example, gelatin, or bubble packings from which the powder can be administered by means of an inhaler. In formulations designed for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 microns or less. Said particle size can be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient can be used. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing suitable quantities of the active component. The unit dosage form may be a packaged preparation, the package containing small amounts of preparation, such as packed tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, wafer, or dragee itself, or it can be the appropriate number of any of those in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.

Method of treatment The compounds of the present invention are valuable modulators of the nicotinic ACh receptor and therefore useful for the treatment of a range of diseases involving cholinergic dysfunction as well as a range of disorders that respond to the activity of receptor modulators. Nicotinic ACh. The compounds can be used in the treatment, prevention, prophylaxis or improvement of a disease, disorder or condition of the central nervous system such as for example: neurodegenerative disorders, memory or cognitive dysfunction, Alzheimer's disease, Parkinson's disease, Huntington, lateral amyotrophic sclerosis, Gilles de la Tourette syndrome, attention deficit hyperactivity disorder, anxiety, depression, mania, manic depression, schizophrenia, obsessive-compulsive disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, memory loss, memory dysfunction, dementia associated with AIDS, senile dementia, peripheral neuropathy, learning deficiency, cognitive deficiency, attention deficiency, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, chronic fatigue syndrome, sleep disorders, pseudodementia, Ganser syndrome, pre-menstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, premature ejaculation, Erectile difficulty, mutism and trichotillomania. The compounds of this invention can also be used in the treatment of inflammatory conditions such as for example: inflammatory conditions of the skin such as acne and rosacea, Chron's disease, inflammatory bowel disease, ulcerative colitis, diarrhea.

In addition, the compounds of the invention can be used in the treatment of diseases associated with smooth muscle contractions such as for example: seizure disorders, angina pectoris, premature labor, seizures, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia. The compounds of this invention may also be useful in the treatment of pain such as, for example, chronic, acute and recurrent pain, postoperative pain, migraine pain or phantom limb pain. The compounds of the present invention can be used to help stop the excessive use of chemical substances such as for example quitting smoking, as well as stop using other products containing nicotine, stop using opioids such as heroin, cocaine and morphine and to stop using benzodiazepines or alcohol. In the context of the present invention "treatment" means both treatment and prevention, prophylaxis and improvement of the symptoms of abstinence and abstinence as well as the resulting treatment in a voluntary decreased consumption of the substance causing addiction. The appropriate dosage range is 0.1-500 milligrams daily, and especially 10-70 milligrams daily administered once or twice per day, depending as is usual on the exact mode of administration, the form in which it is administered, the indication to which the administration is directed, the subject involved and the body weight of the subject involved, and also the preference and experience of the doctor or veterinarian in charge. i.p. means intraperitoneally, which is a well-known route of administration. p.o. means peroral, which is a well-known administration route. The invention therefore comprises the following alone or in combination: The use of a compound as mentioned above in which the disease to be treated is pain, a disease in the central system, a disease caused by smooth muscle contraction, neurodegeneration , inflammation, symptoms of excessive use or withdrawal of chemical substances caused by the cessation of consumption of the chemical. The use as mentioned above in which a disease in the central system is Alzheimer's disease, Parkinson's disease, memory dysfunction or attention deficit hyperactivity disorder. The use as mentioned above, wherein the disease to be treated is excessive use or withdrawal symptoms of chemical substances caused by the discontinuation in the ingestion of the chemical, said excessive use of the chemical substance is smoking or the use of other products that contain nicotine, and withdrawal symptoms caused by the discontinuation of the use of nicotine-containing products. The method as mentioned above where pain is treated, a disease in the central or peripheral system, a disease caused by smooth muscle contraction, neurodegeneration, inflammation, symptoms of excessive use or withdrawal of chemical substances caused by the cessation of consumption of chemical substances, such as quitting smoking. The method as mentioned above in which are treated the symptoms of excessive use or withdrawal of chemical substances caused by the cessation of consumption of the chemical, such excessive use of chemical substance is smoking or the use of other products containing nicotine and withdrawal symptoms caused by cessation of use of products containing nicotine. A method as mentioned above in which a disease is treated in the central or peripheral system, said disease is Alzheimer's disease, Parkinson's disease, memory dysfunction or attention deficit hyperactivity disorder. The following examples will illustrate the invention in greater detail, however, they do not represent a limit.

EXAMPLES General: All reactions involving reagents or intermediaries sensitive to air were carried out under nitrogen and in anhydrous solvents. Magnesium sulfate was used as a drying agent in the treatment processes and the solvents were evaporated under reduced pressure.

Method A (±) -1-Methyl-3-oxy- (3-pyridyl) -pyrrolidine (1a) A solution of 3-oxi- (3-pyridyl) -pyrrolidine (3.0 g, 18.3 mmol), acid Formic (25.3 g, 99%), formaldehyde (5.5 g, 37%) and water (50 ml) was stirred under reflux for 15 hours. The mixture was evaporated, and sodium hydroxide (60 ml, 4 M) was added, and the product was extracted twice with ethyl acetate (60 ml). The product was isolated as an oil. Yield 2.5 g, 77%. (±) -1-Methyl-3-oxy- (3-pyridyl) -azetidinoxalic acid salt Prepared in accordance with method A. P.f. 166.9-170 ° C. (+) - 1 -Methyl-3-oxy- (3-pyridyl) -piperidine (3a) Prepared according to method A. Isolated as an oil. (±) -1-Methyl-3-oxi- (5-chloro-3-pyridyl) -pyrrolidone (4a) Prepared according to method A. Isolated as an oil.

Acid salt (±) -1-methyl-3-oxy- (5-chloro-3-pyridyl) -piperidine-fumaric acid (5a) Prepared in accordance with method A. P.f. 137.2-139.4 ° C. (±) -1 -Methyl-3-oxy- (2-chloro-3-pyridyl) -pperidine (6a) Prepared according to method A. Isolated as an oil.

Acid salt (±) -1-methyl-4-oxy- (3-pyridyl) -homopiperidinfumárico (7a) Prepared in accordance with method A. P.f. 76-78 ° C. (±) -1-Methylene-4-oxy- (5-chloro-3-pyridyl) -homopiperidine-fumaric acid salt (8a) Prepared in accordance with method A. P.f. 113-116 ° C.

Method B (±) -3-Oxi- (3-pyridyl) -pyrrolidine (1 b) To a mixture of (±) -3-oxy- (3-pyridyl) -1-fer-butoxycarbonylpyrrolidine ( 16.0 g, 60.8 mmol) and dichloromethane (300 mL) was added trifluoroacetic acid (97 mL) and stirred for 6 hours followed by evaporation. Methanol (50 ml) was added and the solution was cooled on ice. Sodium hydroxide (10 g, 0.25 mol) was added slowly and the mixture was stirred for 15 hours. The volume of the solvent was reduced to 10 ml, and dichloromethane (30 ml) was added. The crude mixture was chromatographed on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) and gave the title compound as an oil. Yield 5.0 g, 50%.

Salt of (±) -3-oxy- (3-pyridyl) -zetidintrifluoroacetic acid (2b) Prepared according to the method B. P.f. 151.8-152.7 ° C. (±) -3-Oxy- (3-pyridyl) -piperidine (3b) Prepared in accordance with method B. Isolated as an oil.

Acid salt (±) - (5-chloro-3-pyridyl) -3-oxy-pyrrolidine-fumaric acid (4b) Prepared according to the method B. P.f. 141.7-143.2 ° C.

Acid salt (±) - (5-chloro-3-pyridyl) -3-oxy-piperidine-fumaric acid (5b) Prepared according to the method B. P.f. 170.5-172.7 ° C.

Acid salt (±) - (2-chloro-3-pyridyl) -3-oxy-pyrimidine (6b) Prepared according to the method B. P.f. 143.9-146.0 ° C. (±) -4-Oxy- (3-pyridyl) -homopiperidn-fumaric acid salt (7b) Prepared according to the method B. P.f. 117-119 ° C. (±) - (5-chloro-3-pyridyl) -4-oxy-homopiperidine (8b) Prepared in accordance with method B. Isolated as an oil.

Method C Diethylazodicarboxylate (16.7 g, 96 mmol) was added dropwise to a mixture of tetrahydrofuran (150 ml) and triphenylphosphine (25.2 g, 96 mmol) and stirred for 0.5 hour. (+) - 3-Hydroxy-1-yer-butoxycarbonylpyrrolidine (12.0 g, 64 mmol) was dissolved in tetrahydrofuran (50 ml) and added dropwise, followed by 3-hydroxypyridine (9.1 g, 96 mmol). The mixture was stirred for 15 hours at 40 ° C. The solvent was evaporated and sodium hydroxide (200 ml, 1 M) was added followed by extraction three times with diethyl ether (200 ml). The solvent was reduced to half the volume by evaporation, and the triphenylphosphine oxide was filtered. The crude mixture was chromatographed on silica gel with dichloromethane and methanol (25: 1). The title compound was obtained. Yield 16.1 g, 100%. (±) -4-Oxi- (3-pyridyl) -1-tert-butoxycarbonylhomopiperidine Prepared in accordance with method C. 1-7er-butoxycarbonyl-azetidn-3-ol A mixture of azetidin-3-ol (7.0 g, 96 mmol) (SS Chattatarjee and DJ Triggle Chem. Commun. 93, (1968)), triethylamine (10.7 g, 106 mmol) and di-fer-butyl bicarbonate (21.0 g, 96 mmol) in dichloromethane (150 ml) was stirred for 15 hours. The crude mixture was evaporated and chromatographed on silica gel with dichloromethane and ethanol (4%). The title compound was obtained. Yield 12.9 g, 78%.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound represented by the general formula (I) any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein m is 1, 2 or 3; n is 1, 2 or 3; R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and R1 represents a 5-6 membered monocyclic heterocyclic group which may be substituted one or more times with substituents that are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3 , OCF3, CN, amino, nitro, -COOR3, -CONR2R3, -NH-CO2R2, NHCO-R2, -OCO-NR2R3; wherein R2 and R3 independently represent hydrogen or alkyl; aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; X-alkyl-Y-alkyl wherein X and Y independently represent O, S, NH, N-alkyl or Se; and alkyl is optionally substituted with alkoxy or thioalkoxy; -X- (alkyl) 0-aryl- wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; monocyclic heterocyclic group -X- (alkyl) 0-5- or 6-membered wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; a monocyclic 5- to 6-membered heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; or R1 represents a bicyclic heterocyclic group, composed of a 5-6 membered monocyclic heterocyclic group fused to a benzene ring, and which may be substituted one or more times with substituents that are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, alkoxy-alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino, nitro, aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; and a 5-6 membered monocyclic heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3 CN, amino, and nitro.

2. - A compound of the formula (I), according to claim 1, further characterized in that R and R1 are attached to an azetidine, pyrrolidine, piperidine or homopiperidine.

3. A compound of the formula (I), according to claim 1, further characterized in that n is 1 and m is 1 or 2; R is hydrogen or C? -4 alkyl; and R1 represents a pyridyl or a substituted pyridyl.

4. A compound of the formula (I), according to claim 1, further characterized in that R1 is 3-pyridyl, 5-chloro-3-pyridyl, 2-cioro-3-pyridyl.

5. A compound of the formula (I), according to claim 1, said compound being: (±) -1-Methyl-3-oxy- (3-pyridyl) -pyrrolidine; (±) -1-Methyl-3-ox- (3-pyridyl) -azetidine; (±) -1-Methyl-3-oxy- (3-pyridyl) -piperidine; (+) - 1-Methyl-3-oxy- (5-chloro-3-pyridyl) -pyrrolidine; (±) -1-Methyl-3-oxi- (5-chloro-3-pyridyl) -piperidine; (±) -1-Methyl-3-ox- (2-chloro-3-pyridyl) -piperidine; (±) -1-Methyl-4-oxy- (3-pyridyl) -homopyperidine; (±) -1 -Methyl-4-oxy- (5-chloro-3-pyridyl) -homopiperidine; (±) -3-Oxy- (3-pyridyl) -pyrrolidine; (±) -3-Oxy- (3-pyridyl) -azetidine; (±) -3-Oxi- (3-pyridyl) -piperidine; (+) - (5-chloro-3-pyridyl) -3-oxy-pyrrolidine; (±) - (5-chloro-3-pyridyl) -3-oxi-piperidine; (±) - (2-chloro-3-pyridyl) -3-oxy-piperidine; (±) -4-Ox- (3-pyridyl) -homopiperidine; or (±) - (5-chloro-3-pyridyl) -4-oxy-homopyperidine; or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to any of claims 1 to 5, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.

7. The use of a compound according to any of claims 1 to 5, for the manufacture of a medicament for the treatment of a disease of a living animal, including a human, whose disease responds to the activity of modulators of nicotinic ACh receptor.

8. The use according to claim 7, wherein the disease to be treated is pain, a disease in the central nervous system, a disease caused by smooth muscle contraction, neurodegeneration, inflammation, symptoms of excessive use or abstinence from chemical substances caused by the cessation of consumption of the chemical substance such as quitting smoking.

9. The use of a compound according to claim 8, wherein a disease in the central nervous system is Alzheimer's disease, Parkinson's disease, memory dysfunction or hyperactivity disorder with attention deficit. SUMMARY OF THE INVENTION The present invention describes compounds represented by the general formula (I) any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein m is 1, 2 or 3; n is 1, 2 or 3; R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and R1 represents a 5-6 membered monocyclic heterocyclic group which may be substituted one or more times with substituents that are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3 , OCF3, CN, amino, nitro, -COOR3, -CONR2R3, -NH-CO2R2, NHCO-R2, -OCO-NR2R3; wherein R2 and R3 independently represent hydrogen or alkyl; aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; -X-alkyl-Y-alkyl wherein X and Y independently represent O, S, NH, N-alkyl or HE; and alkyl is optionally substituted with alkoxy or thioalkoxy; -X- (alkyl) 0-aryl- wherein 0 is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; monocyclic heterocyclic group -X- (alkyl) 0-5- or 6- members in which o is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; a monocyclic 5- to 6-membered heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; or R1 represents a bicyclic heterocyclic group, composed of a 5- to 6-membered monocyclic heterocyclic group fused to a benzene ring, and which may be substituted one or more times with substituents that are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, alkoxy-alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino, nitro, aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3, CN, amino and nitro; and a 5- to 6-membered monocyclic heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF3, OCF3 CN, amino and nitro; The compounds of the invention are useful as nicotinic ACh receptor ligands.