MXPA99011081A - 8-azabicyclo(3,2,1)oct-2-ene and octane derivatives as cholinergic ligands at nicotinic ach receptors - Google Patents

Abstract

The present invention discloses compounds of formula (1) any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof;wherein - - - - is a single or a double bond;R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl;and R1 is (a), wherein R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amino;or aryl which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, aminoacyl, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group;a monocyclic 5 to 6-membered heteroaryl group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group;or a bicyclic heteroaryl group composed of a monocyclic 5 to 6 membered heteroaryl group fused to a benzene ring or fused to another monocyclic 5 to 6-membered heteroaryl, all of which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group. The compounds of the invention are useful as nicotinic ACh receptor ligands.

Description

DERIVATIVES OF 8-AZABICICLO.3.2.1) OCT-2-ENO AND -OCTANO AS COLINERGIC LIGANDS IN THE ACH RECEIVERS NICOTINIC The present invention relates to derivatives of 8-azabicyclo [3.2.1] oct-2-ene and -octane 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 knowledge, 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 coiinergic 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 (Merriam et al., Psychiatrics Annals, Vol. 23, pp. 171-178, 1993 and Adler et al., Biol Psichiatry, 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.P. Pharmacodyne, Vol.Un 296. p.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 chemicals, 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 is therefore very likely, that the compounds that possess this receptor modulator character also present 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 , amyotrophic lateral 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. The structural analogues close to the compounds of the present invention are described in EP 122580 which describes pyrimidine derivatives as dihydrofolate reductase inhibitors useful against bacterial and anti-malarial infections. GB2298647 describes bridged piperidines which promote the release of growth hormone. WO 97/13770 describes inhibitors of the reuptake of the neurotransmitter monoamine. EP 0498331 which describes N- (aryloxyalkyl) -heteroaryl-8-azabicyclo (3.2.1.) Octanes as antipsychotic agents and as inhibitors of serotonin reuptake. Reference J. Med. Chem. 1995, 38, 1998-2008, describes s-ligands with potential anxiolytic activity. The reference J. Org. Chem. 1994, 59, 2164-2171, describes abbreviated congeners of ibogaine. There is therefore a great need to develop modulators of nicotinic ACh receptor with a more favorable pharmacological profile. A favorable pharmacological profile means, for example: a high selectivity of binding to the neuronal nAChR subtypes, for example subtype a7. - A low affinity towards the muscular subtype.

- An induction of cell survival. - An oral efficacy in vivo (model in rats) of excitement / attention. - A low toxicity in vivo. - A non-mutagenic compound. In accordance with the present invention, valuable modulators of nicotinic cholinergic receptors are provided. Certain compounds that are antagonists at the nicotinic ACh receptor may be useful for the treatment of transient anoxia and induced neurodegeneration.

OBJECTIVES OF THE INVENTION It is an object of the present invention to provide novel derivatives of 8-azabicyclo [3.2.1] oct-2-ene and -octane which are useful for the treatment of a range of diseases or conditions or disorders characterized by diminished cholinergic function or that respond to the activity of nicotinic ACh receptor modulators. 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.

It is still another object of the invention to provide novel compounds that have some, if not all, of the following favorable characteristics: - High selectivity of binding to neuronal nAChR subtypes, for example subtype 7. - A low affinity for the muscular subtype. - An induction of cell survival. - An in vivo oral efficacy of excitement / attention - A low toxicity in vivo. - A non-mutagenic compound Hereinafter, other objectives will become apparent to one skilled in the art.

THE PRESENT INVENTION In the context of this invention "treatment" covers treatment, prevention, prophylaxis or improvement and "disease" covers a disease or disorder or condition. In the context of this invention "modulator" covers agonists, partial agonists, antagonists and allosteric modulators. In the context of this invention "disorders in the central nervous system" covers for example: neurodegenerative disorders, memory or cognitive dysfunction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Gilles de la Tourette syndrome , hyperactivity disorder with attention deficit, 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 deficit, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, chronic fatigue syndrome, disorders of sleep, pseudodementia, Ganser syndrome, syndrome premenstrual, late luteal phase syndrome, chronic fatigue syndrome, premature ejaculation, erection difficulty, mutism and trichotillomania. In the context of this invention "inflammatory conditions" covers for example: inflammatory conditions of the skin such as acne and rosacea, Chron's disease, inflammatory bowel disease, ulcerative colitis, diarrhea. "Diseases associated with smooth muscle contractions" covers for example: seizure disorders, angina pectoris, premature birth, seizures, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia. In the context of this invention "pain" covers for example chronic, acute and recurrent pain, postoperative pain, migraine pain or phantom limb pain.

"Excessive use of chemical substances" covers smoking as well as the use of other products that contain nicotine, the use of opioids, such as heroin, ***e and morphine, the use of benzodiazepines or alcohol. In this context, "treatment" covers treatment, prevention, prophylaxis, and improvement of withdrawal and abstinence symptoms as well as treatment that results in decreased voluntary consumption of the substance causing the addiction. The invention then comprises, inter alia, the following, alone or in combination: A compound having the formula any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein "^ is a single bond or a double bond, R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and R1 is wherein R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amino; or aryl which can be substituted one or more times with substituents which are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino , aminoacyl, nitro, aryl and a monocyclic heteroaryl group of 5 to 6 members; a 5-6 membered monocyclic heteroaryl group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a 5- to 6-membered monocyclic heteroaryl group, or a bicyclic heteroaryl group composed of a 5-6 membered monocyclic heteroaryl group fused to a benzene ring or fused to another monocyclic heteroaryl from 5 to 6 members, and which may be substituted one or more times with substituents selected from the group consisting of: alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3 , OCF3, CN, amino, nitro, aryl and a monocyclic heteroaryl group of 5 to 6 members. A preferred embodiment of the invention is a compound of formula 1 wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and R1 is wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amino; or aryl which is substituted one or more times with substituents that are selected from the group consisting of cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, OCF3 > CN amino, aminoacyl, nitro, aryl and a monocyclic heteroaryl group of 5 to 6 members; A 5-6 membered monocyclic heteroaryl group which can be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, nitro, aryl and a 5-6 membered monocyclic heteroaryl group; or A bicyclic heteroaryl group composed of a 5 to 6 membered monocyclic heteroaryl group with a heterogeneous atom, fused to a benzene ring or fused to another monocyclic heteroaryl of 5 to 6 members, all of which may be substituted one or more times with substituents which are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a monocyclic heteroaryl group of to 6 members. Another preferred embodiment of the invention is a compound of formula 1 wherein R is hydrogen, methyl, ethyl or benzyl; R1 is acetyl, 2-methoxyphenium, 2-naphthyl, 3-acetamidophenyl, 2-selenophenyl, 3-pyridyl, 3- (6-methoxy) pyridyl, 3- (6-chloro) pyridyl, 2-thiazolyl, 3-thienyl, 2 -thienyl, 2- (3-methoxymethyl) thienyl, 2-furyl, 3-furyl, 2- (3-bromo) thienyl, 3- oro-thien-2-yl, 3- (3-furyl) -2-thienyl , 3-quinolinyl, 3-benzofuryl, 2-benzofuryl, 3-benzothienyl, 2-benzothienyl, 2-benzothiazolyl, 2-thieno [3,2-b] thienyl, thieno [2,3-bjthienyl, 2- (3-bromo) benzofuryl or 2- (3-bromo) benzothienyl. A further embodiment of the invention is a compound as indicated above which is (±) -8-benzyl-3- (3-pyridyl) -8-azabicynic [3.2.1] oct-2-ene; (+) - 8-methyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -8-benzyl-3- (3-quinolinyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3 (3-benzofuryl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 (3-benzothienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 (2-thiazolyl) -8-methyl-8-azabicynic [3.2.1] oct-2-ene; (±) -8-methyl-3- (2-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (+) - 8-methyI-3- (3-thienyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -8-methyl-3- (2-naphthyl) -8-azabicyclo [3.2.1] oct-2-ene; Exo-8-methyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] octane; (±) -8-H-3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ene; (+) - 8-methyl-3- [3- (6-methoxy) pyridyl] -8-azabicyclo [3.2.1] oct-2-ene; (±) -3-acetyl-8-methyl-8-azabicynic [3.2.1] oct-2-ene; (±) -8-methyl-3- [3- (6-chloro) pyridi-8-azabicyclo [3.2.1] oct-2-ene; (±) -3H 2-benzofuryl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 2-benzothienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- < 3-acetamidophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- 3-aminophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- 2-thienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 2- (3-methoxymethylthiol)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3H 2-benzothiazolyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 2-furyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 2-thieno [3.2-b] thienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 2-thieno [3.2-b] thienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 2-selenophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- 2-benzofurii) -8-H-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 3- (3-furyl) -2-thienyl] -8-H-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 2-benzofuryl) -8-etiI-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- 2- (3-Bromothienyl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- 2- (3-bromobenzofuryl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- 2- (3-bromobenzothienyl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; 3- [2- (3-chlorothienyl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; or (±) -3- [3- (3-furyl) -2-thienyl] -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; or a pharmaceutically acceptable addition salt thereof. A pharmaceutical composition, comprising a therapeutically effective amount of a compound as the above, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. The use of a compound indicated above for the manufacture of a medicament for the treatment or prevention of a condition or disorder or disease of the body of a living animal, including a human, whose condition or disorder or disease responds to the activity of modulators of nicotinic ACh receptor. The use of a compound as indicated above, wherein the disease to be treated is pain, a disease in the central nervous system, a disease caused by smooth muscle contraction, neurodegeneration, inflammation, excessive use of chemical substances or symptoms of abstinence caused by the fact of stopping the chemical substance. The use indicated above, wherein the disease is a disease in the central nervous system, said disease being Alzheimer's disease, Parkinson's disease, memory dysfunction or hyperactivity disorder with attention deficit. The use indicated above, wherein the disease to be treated is the excessive use of chemical substances or withdrawal symptoms caused by the fact of stopping the chemical, such excess being the use of the chemical smoking, or using other products containing nicotine and said withdrawal symptoms caused by the fact of stopping the use of nicotine-containing products; A method for the preparation of the compounds indicated above, comprising a) the step of reacting a compound having the formula wherein R is as defined above, with a compound of the formula R1-Li, wherein R1 is as defined above, followed by dehydration of the compound obtained; b) the step of reacting the compound having the formula wherein R is as defined above, with a compound of the formula R1-X, wherein R1 is as defined above and X is halogen, boronic acid or trialkylstannyl; or c) the step of reducing a compound that has the formula wherein R1 is as defined above; A method for treating a disease in the body of a living animal, including a human, whose disease responds to the activity of modulators of the nicotinic ACh receptor, comprising the step of administering to such a living animal body, including a human, in need thereof, a therapeutically effective amount of a compound indicated above; The method indicated above, where pain is treated, a disease of the central nervous system, neurodegeneration, inflammation, excessive use of chemical substances, withdrawal symptoms from the fact of stopping the substances that cause addiction, or an illness caused by smooth muscle contractions. The method indicated above, which deals with the excessive use of chemical substances or the withdrawal symptoms caused by the fact of stopping the use of chemical substances, said excessive use of chemical substance being smoking or using another product containing nicotine and said symptoms of abstinence caused by the fact of stopping using products that contain nicotine.

The use indicated above, wherein a disease of the central nervous system is treated, said disease being Alzheimer's disease, Parkinson's disease, memory dysfunction or hyperactivity disorder with attention deficit. Examples of pharmaceutically acceptable addition salts include the organic and inorganic acid addition salts such as the hydrochloride, bromohydrate, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate, stearate, succinate, glutamate, glycolate, p-toluenesulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and acetate. Such salts are formed by methods well known in the art. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates for obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Halogen is fluoro, chlorine, bromine or iodine. Alkyl means a straight chain or a branched chain of one to six carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl; the preferred groups being methyl, ethyl, propyl and isopropyl. 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, which includes at least one double bond, for example, but not limited to ethenyl, 1,2 or 2,3-propeny, 1,2-, 2,3- or 3,4-butenyl. Alkynyl means a group of two to six carbon atoms, which includes at least one triple bond, for example, but not limited to ethynyl, 1, 2- or 2,3-propynyl, 1, 2- or 2,3- or 3,4-butinyl. Cycloalkylalkyl means cycloalkyl as indicated above and alkyl as indicated above, meaning for example cyclopropylmethyl. Alkoxy is O-alkyl, wherein alkyl is as defined above. Cycloalkoxy is O-cycloalkyl wherein cycloalkyl is as defined above. Thioalkoxy is S-alkyl, wherein alkyl is as defined above. Thiocycloalkoxy is S-cycloalkyl, wherein cycloalkyl is as defined above. Amino is NH2 or NH-alkyl or N- (alkyl) 2, wherein alkyl is as defined above. Acyl is (C = O) -R ° or (C = S) -R ° where R ° is alkyl, alkoxy, aryl or aryloxy; wherein alkyl and alkoxy are as defined above and aryl and aryloxy will be defined later.

Aminoacyl is -NH-acyl, wherein acyl is as defined above. A 5- to 6-membered monocyclic heteroaryl group contains one, two, three or four heterogeneous atoms and includes for example, oxazol-2-ylo, oxazol-4-yl, oxazol-5-yl, isoxazoI-3-yl , isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazoI-5-yl, 1, 2,4-oxadiazol-3-yl, 1,4-oxadiazol-5-yl, 1,4-thiadiazo-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-thiadiazol-4-yl, 1-imidazolyl, 2-imidazoyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolid, 3-pyrrolid, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl and 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolium, tetrazolyl. A bicyclic heteroaryl group composed of a 5- to 6-membered monocyclic heteroaryl group and a fused benzene ring or other 5- to 6-membered monocyclic heteroaryl group means a 5- to 6-membered monocyclic heteroaryl group as indicated above, which is fused to a benzene ring or fused to a 5- to 6-membered heteroaryl as indicated above, including, for example, 2-, 3-, 4-, 5-, 6-, 7-benzofuranyl, 1-, 2- , 4-, 5-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-quinolinyl and 1 -, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, thieno [3,2-bjthienyl, thieno [2,3-b] thienyl. Aryl is an aromatic hydrocarbon, such as phenyl and naphthyl.

Aryloxy is -O-aryl wherein aryl is as defined above. 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. It will be appreciated by those skilled in the art that the compounds of the present invention contain several chiral centers and that such compounds exist in the form of isomers (ie, enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures. The racemic forms can be resolved at the optical antipodes by known methods, for example, by separating the diastereomeric salts thereof with an optically active acid, and releasing the optically active amine compound by treating it with a base. Another method to solve the racemates in their optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can thus be resolved in their optical antipodes, for example, by fractional crystallization of the 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 by reaction of the compounds of the present invention with an optically active activated carboxylic acid such as those obtained from (+) or (-) phenylalanine, (+ ) or (-) phenylglycine, (+) or (-) cananic acid or by the formation of diastereomeric carbamates by reaction of the compounds of the present invention with an optically active chloroformate or the like. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used and will be apparent to the average worker skilled in the art. Such methods include those described by J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions," John Wiley & 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 those described in the following examples. 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 methods such as extraction, crystallization, distillation, chromatography and the like.

BIOLOGY The 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 subunits 0.4 and β2- 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 KCl, 1 mM MgCl2 and 2.5 mM of CaCl2 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 ml g per gram of original tissue) and used for binding tests.

Test Aliquots of 500 μl of the homogenized material were added to 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 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. Neurosci., 5, 1307-1315 (1985)). 3H- -bungarotoxin marks the nAChR formed by the isoform 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 homo-oligomer α 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 KCl, 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-a-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% of 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 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.

In vitro inhibition of 3H-epibatidine binding Epibatidine is an alkaloid that was first isolated from the skin of the Ecuadorian frog Epipedobates tricolor and was 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 nicitinic 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 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 2.0 ml aliquots 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. The results are given as IC50 values; the concentration (μM) that inhibits the binding of the radioactive ligand by 50%.

The results of the test for a compound of the invention are presented below: (the numbers of the compound refer to the examples) PHARMACEUTICAL COMPOSITIONS In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention. Although a chemical compound of the invention to be used in therapy can be administered in the form of the chemical compound without treatment, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical composition together with one or more auxiliaries. , excipients, vehicles and / or diluents.

In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical 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 ingredients and / or prophylactics. The vehicle (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not be harmful to the subject receiving it. The pharmaceutical compositions of the invention may be those suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or those in a form appropriate for administration by inhalation or insufflation. The chemical compound of the invention, together with a conventional auxiliary, vehicle, or diluent, can thus be placed in the form of a pharmaceutical composition and unit doses thereof, and in such form can be used as solids, such as tablets or filled capsules, or 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). Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any appropriate effective amount of the active ingredient commensurate with the daily dosage range. usable intended. The chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, any of a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention. To prepare pharmaceutical compositions from chemical compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, wafers, 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 the powders, the carrier is a finely divided solid which is mixed with the finely divided active component. In tablets, the active component is mixed with the vehicle having the necessary binding capacity in appropriate proportions and compacted in the desired shape and size.

The powders and tablets preferably contain from five or ten to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, a low melting point wax, cocoa butter and the like. The term "preparation" is designed 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 a vehicle, is surrounded by a vehicle, which is thus in association with the same. Similarly, wafers and pills are included. Tablets, powders, capsules, pills, wafers and lozenges 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 or cocoa butter glycerides, is first melted and the active component dispersed homogeneously therein, such as by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and therefore solidify. Suitable compositions for vaginal administration may be presented as ovules, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers, which are known to be suitable in the art.

Liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be formulated as solutions in aqueous solution of polyethylene glycol. The chemical compound according to the present invention can thus be formulated for parenteral administration (for example by injection, for example bolus injection or continuous infusion) and can be presented in unit dosage forms in ampoules, pre-filled syringes and pre-filled syringes. -filled, small volume infusion or in multiple dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oil 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 lyophilization of the solution, to reconstitute it with an appropriate vehicle, for example sterile, pyrogen-free water, before use. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding the appropriate 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 a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agent. Also included are solid form preparations that are designed to be converted, briefly before use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffer solutions, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. For topical administration to the epidermis, the chemical compound according to the invention can be formulated as ointment, cream or lotions, or as a transdermal patch. Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of appropriate thickeners and / or gelling agents. The lotions can 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. Compositions suitable for topical administration in the mouth include lozenges consisting of the active agent in a flavored base, usually sucrose and acacia or tragacanth, the lozenges comprise the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprise the active ingredient in an appropriate liquid vehicle. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or sprinkler. The compositions may be provided in the form of single doses or in the form of multiple doses. In the latter case of a dropper or pipette, this may be achieved by administering to the patient an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this can be achieved, for example, by means of a spraying pump. Administration to the respiratory tract can also be achieved by an aerosol formulation in which the active ingredient is supplied in a pressurized package with a prqpelent such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other appropriate gas. The aerosol may also conveniently contain a surfactant agent such as lecithin. The dose of drug can be controlled by providing 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 an appropriate 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 forms for example in capsules or in cartridges for example of gelatin or bubble pack (blister packs) from which the powder can be administered by means of an inhaler. In compositions designed for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size, for example of the order of 5 microns or less. A particle size as such can be obtained by methods known in the art, for example by micronization. When desired, compositions adapted to provide 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 the appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packaged tablets, capsules and powders packaged in vials or in ampoules. In addition, the unit dosage form can be a capsule, tablet, wafer or a tablet itself, or it can be the appropriate number of either of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are the preferred compositions. The doses administered should, of course, be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the desired result. It is currently contemplated that compositions containing from 0.1 to 500 mg of active ingredient per unit dose, preferably from 1 to about 100 mg, with more preferred from 1 to about 10 mg, are suitable for therapeutic treatments. A satisfactory result can be obtained, in certain cases, in a dose as low as 0.005 mg / kg i.v. and 0.01 mg / kg p.o. The upper limit of the dosage range is about 10 mg / kg i.v. and 100 mg / kg p.o. Preferred ranges are from 0.01 to about 1 mg / kg i.v. and from about 0.1 to about 10 mg / kg p.o.

TREATMENT METHOD The compounds of the present invention are valuable modulators of nicotinic ACh receptor and therefore useful for the treatment of a gamma of diseases involving cholinergic dysfunction as well as a gamma of disorders that respond to the activity of nicotinic receptor modulators of 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 deficit, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia , post-traumatic syndrome, social phobia, fati syndrome chronic cancer, sleep disorders, pseudodementia, Ganse 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, ***e 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 following examples will further illustrate the invention, however, these should not be considered as limitations.

EXAMPLES General All reactions involving reagents or intermediates 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 1a: Fumaric acid salt of (+) - 8-benzyl-3- (3-pyridyl-8-azabicyclo-r3.2.1loct-2-ene to a mixture of 3-bromopyridine (11.0 g, 69.7 mmol) and diethyl ether (200 ml), butyllithium in hexanes (2.5 M, 30.7 ml, 76.7 mmoles) was added at -70 ° C. The mixture was stirred at -70 ° C for 1 hour. added 8-benzyl-8-azabicyclo [3.2.1] octan-3-one (15.0 g, 69.7 mmol) dissolved in diethyl ether (80 ml) and stirred for 1 hour.The reaction mixture was allowed to warm to room temperature overnight, aqueous sodium hydroxide (1M, 200 ml) was added and the diethyl ether was separated The aqueous phase was extracted three times with ethyl acetate (100 ml) The organic phases were mixed. -8-benzyl-3-hydroxy-3- (3-pyridyl) -8-azabicyclo [3.2.1] octane after trituration with petroleum ether, yield 7.0 g, 34%, a mixture of endo-8- benzyl-3-hydroxy-3- (3-pyridyl) -8-azabicyclo [3.2.1] octane (3.0 g, 10.2 mmol), thionyl chloride (9 ml, 1 23 mmol) and tetrahydrofuran (100 ml) was stirred at 50 ° C for 0.5 h. The mixture was evaporated and combined with potassium hydroxide (4.6 g, 82.0 mmol), ethanol (25 ml) and water (25 ml) and stirred for 5 minutes. The ethanol was evaporated and water (50 ml) was added, followed by double extraction with ethyl acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the free base of the title compound, yield 2.2 g, 78%. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. p.f. 142-146 ° C. 2a: fumaric acid salt of (±) -8-methyl-3- (3-pyridyl) -8-azabicyclo3.2.noct-2-ene Prepared from 8-methyl-8 -azab-cyclo [3.2.1] octan-3-one in accordance with method a. P.f. 124-126 ° C. 3a: fumaric acid salt of. +) - 8-? T? Ethyl-3 - (, 3-quinolinyl.-8-azabicyclo r3.2.11oct-2-ene) Prepared from 8-methyl-8-azabicyclo [3.2.1] octan-3-one in accordance with method a.Pf 140.8-143.8 ° C. 4a: (+) - 3- (3-benzofuryl) -8-azabicyclo fumaric acid salt Prepared in accordance with method a. P.f. 140.9-142.8 ° C. 5a: fumaric acid salt of, +) - 3- (3-benzothienyl) -8-methyl-8-azabicyclo3.2.poct-2-ene. Prepared in accordance with method a. P.f. 146.6-149.5 ° C. 6a: fumárico acid salt of, ±) -3- (2-thiazolyl) -8-methyl-8-azab¡c¡clo í3.2.1loct-2-ene. Prepared from 8-methyl-8-azabicyclo [3.2.1] octan-3-one in accordance with method a. P.f. 196.3-198.5 ° C. 7a: fumaric acid salt of. ±) -8-methyl-3- (2-methoxyphenD-8-azabicyclo r3.2.noct-2-ene. Prepared from 8-methyl-8 -azabicyclo [3.2.1] octan-3-one in accordance with method a. 8a: hydrochloric acid salt of (±) -8-methyl-3-.3-t.eniD-8-azabicyclo r3.2.1loct-2-ene. Prepared from 8-methylene-8-azabicyclo [3.2.1] octan-3-one according to method a. P.f. 117-118.5 ° C. 9a: hydrochloric acid salt of (±) -8-methyl-3- (2-naphthyl) -8-azabicyclo r3.2.noct-2-ene. Prepared from 8-methyl-8-azabicyclo [3.2.1] octan-3-one according to method a; P.f. 259-264 ° C. 10a: exo-8-methyl-3- (3-pyridyl) -8-azabicyclo-dichlorohydrate .3.2.11 octane. A mixture of endo and exo-3-hydroxy-8-methyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] octane (method a) (1.5 g, 6.9 mmoles), Raney nickel (20.0 g, 50% suspension in water) and 50 ml of ethanol was stirred at reflux for 15 hours. The crude mixture was filtered followed by chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) which yielded the product as the free base. The product was converted to the title compound by the addition of hydrogen chloride in ethanol. P.f. 275-280 ° C. Yield 0.55 g, 29%. 11a: endo-3-hydroxy-3- (3-pyrid-8-8-tert-butoxycarbonyl-8-azabicyclo3.2.n octane) A mixture of endo-8-benzyl-3-hydroxy-3- ( 3-pyridyl) -8-azabicyclo [3.2.1] octane (3.0 g, 10.2 mmol), palladium on carbon (5%, 0.80 g), concentrated hydrochloric acid (2 ml) and ethanol (75 ml) was stirred under hydrogen during 15 hours The crude mixture was filtered through celite and evaporated to dryness and stirred with triethylamine (4.1 g, 40.0 mmol), di-tert-butoxycarbonyl anhydride (1.75 g, 8.0 mmol) and dichloromethane (50 mL) for 3.5 The crude mixture was evaporated and then chromatographed on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) which yielded the title compound, Mp 90-92 ° C, yield 2.8 g, 90% 12a: (±) -3- (3-pyridyl) -8-tert-butoxycarbonyl-8-azab-1-chloro3.2.11oct-2-ene A mixture of endo-3-hydroxy-3- ( 3-pyridyl) -8-tert-butoxycarbonyl-8-azabicyclo [3.2.1] octane (2.0 g, 6.6 mmol), thionyl chloride (6 ml, 82 mmol) and tetrahydrofuran (100 ml) was stirred at 50 ° C. for 0.5 hours. The mixture was evaporated and combined with potassium hydroxide (3.0 g, 53 mmol), ethanol (20 ml) and water (20 ml) and stirred for 10 minutes. The ethanol was evaporated and water (50 ml) was added. The mixture was extracted twice with ethyl acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound as an oil. Yield 0.43 g, 23%.

Method b 1b: Fumaric acid salt of (+) - 8-H-3- (3-pyridyl) -8-azabicyclo It was stirred (±) -3- (3-pyridyl) -8- tert-butoxycarbonyl-8-azabicyclo [3.2.1] oct-2-ene (0.40 g, 140 mmol) in a mixture of trifluoroacetic acid (3.2 g, 28 mmol) and dichloromethane overnight. Aqueous sodium hydroxide (100 mL, 1 M) was added followed by extraction with dichloromethane (100 mL) three times. Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the pure title compound. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Yield 0.13 g, 31%. P.f. 175-176 ° C. 2b: (+) - 8-methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo3.2.11 oct-2-ene. To 8-methyI-8-azabicynic [3.2.1] octan-3-one (12.65 g, 90.9 mmol) in tetrahydrofuran (300 ml), sodium bis (trimethylsilyl) amide in tetrahydrofuran (77.5) was added at -70 ° C. ml, 77.5 mmoles). The reaction mixture was stirred for 30 minutes at -70 ° C. N-PhenyIbis (trifluoromethansulfonamide) (32.5 g, 90.9 mmol) in tetrahydrofuran (200 ml) was added at -70 ° C. The reaction mixture was allowed to reach room temperature slowly and was stirred overnight. Aqueous sodium hydroxide (0.1M, 500 ml) was added and the mixture was extracted twice with ethyl acetate (200 ml). Chromatography on silica gel with dichloromethane and 10% ethanol as solvent yielded the title compound as an oil. Yield 16.2 g, 45%. 3b: (±) -8-methyl-3-r3- (6-methoxy) pyridin-8-azabicyclo3.2.n oct-2-ene A mixture of (±) -8-methyl- 3-Trifluoromethanesulfonyl-oxy-8-azabicyclo [3.2.1] oct-2-ene (3.0 g, 12.2 mmol), hexamethyldithine (4.0 g, 12.2 mmol), bis (trphenylphosphine) palladium (II) dichloride (0.43 g, 0.61 mmol) and lithium chloride (0.52 g, 12.3 mmol) was stirred in 1,4-dioxane (25 ml) at 70 ° C for 2 hours. Then 3-bromo-6-methoxypyridine (4.6 g, 24.4 mmol) was added followed by stirring at reflux overnight. The solvent was evaporated and aqueous sodium hydroxide (30 ml, 1M) was added followed by extraction three times with ethyl acetate (30 ml). Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound as an oil. Performance 1.0 g, 36%. 4b: Fumaric acid salt of (±, -3-acetyl-8-methyl-8-azabicyclo A mixture of (±) -8-methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo [3.2.1] oct-2-ene (2.0 g, 7.4 mmol), 1-methoxy-1-trimethylstannylethylene (2.45 g, 11.1 mmoies), bis (triphenylphosphine) palladium (II) dichloride (0.26 g, 0.37 mmol) and lithium chloride ( 0.31 g, 7.4 mmol) was stirred in tetrahydrofuran (30 ml) under reflux overnight The solvent was evaporated.Sodium hydroxide (40 ml, 1M) was added and the mixture was extracted with ethyl acetate. 148. 5-150 ° C. Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the fumaric acid salt of (±) -3- (1-methoxy-1-ethenyl) -8-methyl-8-azabicicio [3.2.1] oct-2-ene (0.23 g, 17%) which was mixed with hydrogen chloride in methanol (10 mL, 4.5 M) and stirred for 10 minutes. The mixture was evaporated to dryness and sodium ethoxide (0.19g, 8.4 mmol) was added. Chromatography of this crude mixture on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Yield 0.21 g, 58%. P.f. 175-176 ° C. 5b: (+) - 8-Methyl-3-r3- (6-chloro) pyridyl-8-azabicyclo3.2.11oct-2-ene fumaric acid salt A mixture of (±) -8-methyl-3 - [3- (6-methoxy) pyridyl] -8-azabicyclo [3.2.1] oct-2-ene (0.50 g, 2.13 mmol) and phosphorus oxychloride (4 ml) in dimethylformamide (5 ml) was stirred throughout the night at 95 ° C. Ice (100 g) and aqueous sodium hydroxide (4 M, 50 ml) were added followed by extraction three times with ethyl acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound as an oil. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Yield 0.35 g, 47%. P.f. 140-142 ° C. 6b: (+ V8-methyl-3-trifluoromethanesulfonyl-oxy-8-azabicyclo3.2.1 joct-2-ene A 8-metii-8-azabicyclo [3.2.1] octan-3-one (9.35 g, 67.2 mmol ) in tetrahydrofuran was added at -70 ° C: sodium bis (trimethylsilyl) amide in tetrahydrofuran (73.9 ml, 73.9 mmol) The reaction mixture was stirred for 10 minutes N-phenylbis (trifluoromethanesulfonamide) was added ( 24.0 g, 67.2 mmol) in tetrahydrofuran at -70 ° C. The reaction mixture was allowed to reach room temperature slowly and was stirred overnight, aqueous sodium hydroxide (0.1 M, 350 ml) and the mixture were added. it was extracted twice with 150 ml of ethyl acetate, chromatography on silica gel with dichloromethane and 10% ethanol as solvent yielded the title compound as a brown oil Yield 11.6 g, 70%.

Method c 1c: fumaric acid salt of (±) -3- (2-benzofuryl) -8-methyl-8-azabicyclo3.2.1.oct-2-ene A mixture of (±) -8-methyl-3-trifluoromethanesulfonyl -oxi-8-azabicyclo [3.2.1] oct-2-ene (1.5 g 6.1 mmole), benzofuran-2-boronic acid (0.99 g, 6.1 mmole), tetrakis (triphenyl-phosphin) -palladium (0) ( 0.07 g, 0.06 mmol) and lithium chloride (4.2 g, 30.5 mmol), potassium carbonate (4.2 g, 30.5 mmol), water (15 ml) and 1,2-dimethoxyethane (15 ml) were refluxed for 1.5 hours. Water (50 ml) was added and the mixture was extracted twice with ethyl acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1), saturated with fumaric acid. Yield 0.24 g, 11%. P.f. 188.3-190.9 ° C. 2c: (+) - 3- (2-benzot¡en¡p-8-methyl-8-azabicyclo3.2.noct-2-ene Prepared according to the method c.P.f. 81.0-83.6 ° C. 3c: fumaric acid salt of (±) -3- (2-acetamidophenyl) -8-methyl-8-azabicyclo3.2.1"loct-2-ene Prepared according to the ac method of 3-acetamidobenzeneboronic acid, Mp 195.3 -196.9 ° C. 4c: fumaric acid salt of (±) -3- (3-aminophen-D-8-methyl-8-azabicyclo3.2.noct-2-ene) A mixture of: (±) -3- (3-acetamidophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene (0.32 g, 1.25 mmol) and hydrochloric acid (25 mL, 25%) were stirred at reflux overnight The mixture was evaporated to dryness Aqueous sodium hydroxide (1 M, 50 ml) was added and the mixture was extracted twice with ethyl acetate (50 ml), Mp 195.3-196.9 ° C. Yield 0.22 g, 52%.

Method d 1d: fumaric acid salt of (+) - 3 - ('2-benzofur-8-methyl-8-azabicycloclo -3.2.noct-2-ene To a mixture of benzofuran (20.0 g, 169.3 mmol) and diethyl ether (200 ml), butyllithium in hexanes (2.5 M, 75 ml, 186 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hours and then cooled to -70 ° C. 8-benzyl-8-azabicyclo [3.2.1] octan-3-one (23.0 g, 169.3 mmol) dissolved in ethyl ether (150 ml) was added at -70 ° C and stirred for 1 hour. The reaction mixture was allowed to warm to room temperature overnight. Water (200 ml) was added and endo and exo-3- (2-benzofuryl) -3-hydroxy-8-methyl-8-azabicyclo [3.2.1] octane were isolated by filtration. Yield 38.7 g, 89%. A mixture of endo and exo-3- (2-benzofuryl) -3-hydroxy-8-methyl-8-azabicyclo [3.2.1] octane (30.0 g, 116.6 mmol), concentrated hydrochloric acid (35 ml) and ethanol ( 300 ml) was stirred at reflux for 1 hour. The solvent was evaporated. Sodium hydroxide (150 ml, 4M) was added and the mixture was extracted twice with ethyl acetate (100 ml). (±) -3- (2-Benzofuryl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene was isolated, yield 18.9 g, 70%. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1), saturated with fumaric acid. P.f. 188.5-191.2 ° C. 2d: (+) - 3- (2-benzofuryl) -8-methyl-8-azabicyclo1.3.2noct-2-ene hydrochloride Prepared according to method d. P.f. > 250 ° C. 3d: fumaric acid salt of (±) -3- (2-thienyl) -8-methyl-8-azabicyclo3.2.1loct-2-ene Prepared in accordance with method d. P.f. 141.5-143.5 ° C. 4d: (±) -3-r2- (3-methoxymethylltin-8-methyl-8-azabicyclo3.2.noct-2-ene) Prepared according to method D. Isolated as an oil. 5d: fumaric acid salt of (±) -3- (2-benzothiazolyl) -8-methyl-8-azabicyclo | "3.2.11oct-2-ene Prepared according to the method d.P.f. 195-196.8 ° C. 6d: fumaric acid salt of (+) - 3-α2- (1-methylindolyl) 1-8-methyl-8-azabicyclo3.2.1loct-2-ene Prepared in accordance with method d, except for the temperature of metalation, at reflux and 1.2 equivalents of tetramethylethylenediamine. 7d: (+) - 3- (2-furin-8-methyl-8-azabicyclo3.2.noct-2-ene Prepared in accordance with method D. Isolated as an oil. 8d: oxalic acid salt of (±) -3- (2-thienor3.2-bientyl) -8-methyl-8-azabicyclo3.2.11oct-2-ene Prepared in accordance with method d. P.f. 48-50 ° C. 9d: oxalic acid salt of (±) -3- (2-thienor3.2-bienthyl) -8-methyl-8-azabicyclo3.2.11oct-2-ene Prepared in accordance with method d. P.f. 46-48 ° C. 10d: (±) -3- (2-selenophenyl) -8-methyl-8-azab-cyclor3.2.1loct-2-ene Prepared in accordance with method d. P.f. 176-8,178.3 ° C.

Method e 1e: fumaric acid salt of (+) - 3- (2-benzofuryl) -8-H-8-azabicyclo [3.2.11oct-2-ene A mixture of (±) -3- (2-benzofuryl) 8-methylal-8-azabicyclo [3.2.1] oct-2-ene (5.4 g, 22.6 mmol), 1-chloroethylchloroformate (5.0 g, 34.7 mmol) and xylene (25 ml) were stirred at reflux for the night. Methanol was added and the mixture was stirred for 2 hours at reflux. Sodium hydroxide (4 M, 50 ml) was added at room temperature and the mixture was extracted with ethyl acetate. Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Yield 2.58 g, 33%. P.f. 201-204 ° C. 2e: fumaric acid salt of (±) -3-r3- (3-furin-2-thienin-8-H-8-azabicyclo [3.2.11oct-2-ene Prepared from: (+ ) -3- [3- (3-furyl) -2-thienyl] -8-methyl-8-azabicyclo [3.2.1] oct-2-ene according to EPf method 187-189 ° C. 3e: fumaric acid salt of (±) -3- (2-benzofuryl) -8-ethyl-8-azabicyclo3.2.11oct-2-ene A mixture of (±) -3- (2-benzofuryl) -8- H-8-azabicyclo [3.2.1] oct-2-ene (1.5 g, 6.7 mmol), bromoethane (0.80 g, 7.3 mmol), diisopropylethylamine (0.87 g, 6.7 mmol) and DMF (50 mL) were stirred for 2 h. hours. Sodium hydroxide (100 ml, 1M) was added, followed by extraction twice with diethyl ether (100 ml). Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1), saturated with fumaric acid. Yield 0.77 g, 31%. P.f. 197-203 ° C.

Method F 1f: fumaric acid salt of. +) - 3-f2- (3-bromothienolIT-8-methyl-8-azabicyclo3.2.noct-2-ene To a solution of 3-bromothiophene (25.0, 153.3 mmoles) in THF (250 ml) was added: lithium diisopropylamide (2M, 168.7 mmol) at -80 ° C. The mixture was stirred for 1 hour at -80 ° C followed by the addition of tropinone (21.3 g, 153.3 mmoles). ) in THF (200 ml) The mixture was stirred at -80 ° C for 1 hour and allowed to reach room temperature overnight.Sodium hydroxide (1 M, 200 ml) was added and extracted three times with diethyl ether (300 ml) The chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded endo and exo-3- [3-bromo- (2-thienyl)] - 3-h; Droxi-8-methyl-8-azabicyclo [3.2.1] octane Yield 8-90 g, 19% A mixture of endo and exo-3- [3-bromo- (2-thienyl)] 3 Hydroxy-8-methyI-8-azabicyclo [3.2.1] octane (8.85 g, 29.3 mmol) and concentrated hydrochloric acid were stirred for 2 h. The hydrochloric acid was evaporated and Sodium hydroxide (1 M, 200 ml) was added and the mixture was extracted twice with ethyl acetate (100 ml). Yield 8.3 g, 100%. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1), saturated with fumaric acid. P.f. 130-132 ° C. 2f: fumaric acid salt of (+) - 3-22- (3-bromobenzofuryl) 1-8-methyl-8-azabicyclo3.2.noct-2-ene Prepared according to the method F. P.f. 161.4-163.3 ° C. 3f: fumaric acid salt of (±) -3-r2- (3-bromobenzothienyl) 1-8-methyl-8-azabicyclo3.2.11oct-2-ene Prepared in accordance with the method F. P.f. 165.0-166.9 ° C. 4f: fumaric acid salt of (±) -3-β2- (3-chlorothienyl) 1-8-methyl-8-azabicyclo [3.2.11oct-2-ene Prepared in accordance with the method F. P.f. 151.5-153.5 ° C. 5f: fumaric acid salt of (±) -3-r3- (3-furyl) -2-t-enin-8-methyl-8-azabiciclof3.2.noct-2-ene A mixture of (±) -3- [2- (3-Bromothienyl)] - 8-ethyl-8-azabicyclo [3.2.1] oct-2-ene (2.0 g, 7.0 mmole), 3-furylboronic acid (0.94 g, 8.4 mmole), tetrakis (triphenylphosphine) -palladium (0) (0.16 g, 0.14 mmol), aqueous potassium carbonate (10.5 ml, 2 M), 1,3-propanediol (2.66 g, 35 mmol), 1,2-dimethoxyethane ( 30 ml) and dioxane (50 ml) was stirred at reflux overnight. Sodium hydroxide (50 ml) was added and the mixture was extracted twice with ethyl acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and concentrated ammonia (89: 10: 1) yielded the title compound. The corresponding salt was obtained by the addition of a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Yield 1.59 g, 59%. P.f. 187.-189 ° C.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula 1 any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; where ^^ is a single link or a double link; R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and R is

O i "wherein R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amino; or aryl which can be substituted one or more times with substituents which are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino , aminoacyl, nitro, aryl and a monocyclic heteroaryl group of 5 to 6 members; a 5-6 membered monocyclic heteroaryl group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a 5- to 6-membered monocyclic heteroaryl group, or a bicyclic heteroaryl group composed of a 5- to 6-membered monocyclic heteroaryl group fused to a benzene ring or fused to another monocyclic heteroaryl from 5 to 6 members, and which can be substituted one or more times with substituents selected from the group consisting of: alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3 , OCF3, CN, amino, nitro, aryl and a 5-6 membered monocyclic heteroaryl group; provided, however, that the compound is not: 3- (1, 2) -benzoisoxazol-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane monohydrate hydrochloride; 3- (1, 2) -benzoisoxazol-3-yl) -8-azabicyclo [3.2.1] octane monohydrate hydrochloride; 3- (6-fluoro-1,2-benzoisoxazol-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane hydrochloride; 3- (6-fluoro-1,2-benzoisoxazol-3-yl) -8-azabicyclo [3.2.1] octane hydrochloride; 3- (1 H-indazol-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane; 3- (1 H-indazol-3-yl) -8-azabicynic [3.2.1] octane; 3- (6-fluoro-1 H -indazol-3-yl) -8-methyl-8-azabicido [3.2.1] octane; 3- (6-fluoro-1 H -indazol-3-yl) -8-azabicyc or [3.2.1] octane; 3- [1,2-benzisothiazol-3-yl] -8-methyl-8-azabicyclo [3.2.1] octane hydrochloride; 3- (1, 2-benzisothiazol-3-yl) -8-azabicyclo [3.2.1] octane; 8-methyl-3- (3,4-dichlorophenol) -8-azabicyclo [3.2.1] oct-2-ene; 8-methyl-3- (4-chlorophenyl) -8-aza-bicyclo [3.2.1] oct-2-ene; 8-methyl-3-phenyl-8-azabicyclo [3.2.1] oct-2-ene; 8-methyl-3- (4-methylphenyl) -8-azabicyclo [3.2.1] oct-2-ene; 8-methyl-3- (4-trifluoromethylene) -8-azabicyclo [3.2.1] oct-2-ene; 8-methyl-3- (4-fluorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; 3- (4-chlorophenyl) -8-aza-bicido [3.2.1] oct-2-ene; 3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; 4-Chloro-2,6-diamino-5- [8- (1-naphthyl) -8-azabicyclo [3.2.1] oct-3-yl] pyrimidine; 4-chloro-2,6-diamino-5- [8- (2-naphthyl) -8-azabicyclo [3.2.1] oct-3-yl] pyrimidine; 8-methyl-3-phenyl-8-azabicyclo [3.2.1] octane; 8-methyl-3- (2-methylphenyl) -8-azabicyclo [3.2.1] oct-2-ene; 8-? Methyl-3- (2-methylphenyl) -8-azabicyclo [3.2.1] octane; 3- (4-fluorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; 8-methyl-3- (1-methylindol-2-yl) -8-azabicyclo [3.2.1 joctane; or 8-methyl-3- (1-methylindol-2-yl) -8-azabicyclo [3.2.1] oct-2-ene. 2. A compound of formula 1 according to claim 1, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and R1 is wherein R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amino; or aryl which is substituted one or more times with substituents which are selected from the group consisting of cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, OCF3, CN, amino, aminoacyl, nitro, aryl and a monocyclic heteroaryl group of 5 to 6 members; a 5-6 membered monocyclic heteroaryl group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, nitro, aryl and a 5-6 membered monocyclic heteroaryl group; or a bicyclic heteroaryl group composed of a 5 to 6 membered monocyclic heteroaryl group with a heterogeneous atom, fused to a benzene ring or fused to another monocyclic heteroaryl of 5 to 6 members, all of which may be substituted one or more times with substituents which are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a monocyclic heteroaryl group of to 6 members.

3. A compound of the formula 1 according to claim 1, wherein R is hydrogen, methyl, ethyl or benzyl; R1 is acetyl, 2-methoxyphenium, 2-naphthyl, 3-acetamidophenyl, 2-selenophenyl, 3-pyridyl, 3- (6-methoxy) pyridyl, 3- (6-chloro) pyridyl, 2-thiazoyl, 3-thienyl, 2-thienyl, 2- (3-methoxymethyl) thienyl, 2-furyl, 3-furyl, 2- (3-bromo) thienyl, 3-chloro-thien-2-yl, 3- (3-furyl) -2- thienyl, 3-quinolinyl, 3-benzofuryl, 2-benzofuryl, 3-benzothienyl, 2-benzothienyl, 2-benzothiazolyl, 2-thieno [3,2-b] thienyl, thieno [2,3-b] thienyl, 2- (3-bromo) ) benzofuryl or 2- (3-bromo) benzothienyl.

4. A compound according to claim 1 which is: (±) -8-benzyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ene; (+) - 8-methyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -8-benzyl-3- (3-quinolinyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3 (3-benzofuryl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 (3-benzothienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3 (2-thiazolyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -8-methyl-3- (2-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -8-methyl-3- (3-thienyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -8-methyl-3- (2-naphthyl) -8-azabicyclo [3.2.1] oct-2-ene; Exo-8-methyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] octane; (±) -8-H-3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -8-methyl-3- [3- (6-methoxy) pyridyl] -8-azabicyclo [3.2.1] oct-2-ene; (±) -3-acetyl-8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (+) - 8-methyl-3- [3- (6-chloro) pyridyl] -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-Benzofuryl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-Benzothienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (3-Acetamidophenol) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (3-aminophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-thienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- [2- (3-methoxymethylthienyl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-Benzothiazolyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-furyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (+) - 3- (2-thieno [3,2-b] thienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-Thieno [3,2-b] thienyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-selenophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-benzofuriI) -8-H-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- [3- (3-Furyl) -2-thienyl] -8-H-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (2-Benzofuryl) -8-etiI-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- [2- (3-Bromothienyl)] - 8-methyl-8-azabicynic [3.2.1] oct-2-ene; (±) -3- [2- (3-Bromobenzofuryl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; (±) -3- [2- (3-Bromobenzothienyl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; 3- [2- (3-chlorothienyl)] - 8-methyl-8-azabicyclo [3.2.1] oct-2-ene; or (+) - 3- [3- (3-furyl) -2-thienyl] -8-methyl-8-azabicyclo [3.2.1] oct-2-ene; or a pharmaceutically acceptable addition salt thereof.

5. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.

6. The use of a compound according to any of claims 1 to 4, for the manufacture of a medicament for the treatment or prevention of a condition or disorder or disease of the body of a living animal, including a human, whose condition or disorder or disease responds to the activity of nicotinic ACh receptor modulators. 7 - The use according to claim 6, wherein the disease to be treated is pain, a disease in the central nervous system, a disease caused by smooth muscle contraction, neurodegeneration, inflammation, excessive use of chemical substances or Withdrawal symptoms caused by the fact of stopping the chemical. 8. The use according to claim 7, wherein a disease in the central nervous system is Alzheimer's disease, Parkinson's disease, memory dysfunction or hyperactivity disorder with attention deficit. 9. The use according to claim 7, wherein the disease is the excessive use of chemical substances or withdrawal symptoms caused by the fact of stopping the chemical substance, said excess being in the use of the chemical smoking. , or use other products containing nicotine and withdrawal symptoms caused by the fact of stopping the use of products containing nicotine. 10. A method for the preparation of the compounds according to claim 1, comprising: a) the step of reacting a compound having the formula wherein R is as defined above, with a compound of the formula R1-L1, wherein R1 is as defined above, followed by dehydration of the compound obtained; b) the step of reacting the compound having the formula wherein R is as defined above, with a compound of the formula R1-X, wherein R1 is as defined above and X is halogen, boronic acid or trialkylstannyl; or c) the step of reducing a compound that has the formula wherein R1 is as defined above. SUMMARY OF THE INVENTION The present invention describes compounds of the formula (1), any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; where is a single or double link; R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyo; and R1 (a) wherein R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amino; or aryl which can be substituted one or more times with substituents which are selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino , aminoacyl, nitro, aryl and a monocyclic heteroaryl group of 5 to 6 members; a 5-6 membered monocyclic heteroaryl group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a 5- to 6-membered monocyclic heteroaryl group, or a bicyclic heteroaryl group composed of a 5- to 6-membered monocyclic heteroaryl group fused to a benzene ring or fused to another monocyclic heteroaryl from 5 to 6 members, of which all may be substituted one or more times with substituents selected from the group consisting of: alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF3, OCF3, CN, amino, nitro, aryl and a 5-6 membered monocyclic heteroaryl group; The compounds of the invention are useful as nicotinic ACh receptor ligands. 1 P99 / 1370F JT / sH * abg * sff * xa aom * mvh * eos.