MXPA98002932A - Azaindol-ethylamine derivatives as agents that join the nicotinic receptor of the acetilcol - Google Patents

Abstract

The compounds of formula I are useful in the treatment of disorders associated with depletion of nicotinic receptors in mammals.

Description

AZAINDOL-ETHYLAMINE DERIVATIVES AS AGENTS THAT JOIN THE NICOTINIC RECEPTOR OF ACETILCOLI A BACKGROUND OF THE INVENTION The present invention relates to heterocyclic compounds. More especially, it relates to azaindola ina compounds of the formula I, discussed below. The compounds of formula I are useful in the treatment of addiction disorders such as the use of tobacco or other products containing nicotine. These compounds are also useful in the treatment of neurogenic disorders and metals such as senile dementia of the Alzheimer type, Parkinson's diseases, hyperactivity disorders in tension, anxiety, obesity, Tourette syndrome and ulcerative colitis. CNS disorders are a type of neuro-logical disorders. CNS disorders may be induced by drugs; it can be attributed to genetic predisposition, infection or trauma; or they may be of unknown etiology. CNS disorders include neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive-affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (ie, disorders that arise from inadequate levels in the release of neurotransmitters, inadequate properties of neuRe rans receptors and / or inadequate interaction between neurotransmitters and neuro-transmitting receptors). Several CNS disorders can be attributed to a cholinergic deficiency, a serotonergic dopaminergic deficiency. CNS disorders of relatively common onset include presenile dementia (early-onset Alzheimer's disease), senile dementia (Alzheimer's type dementia, Parkinsonism, including Parkinson's disease, Huntington's chorea, dyskinesia, hyperkinesia, mania, deficit disorders, attention, anxiety, dyslexia, schizophrenia and Tourette syndrome, senile dementia of Alzheimer's type (DSTA) in a debilitating neurodegenerative disease, which fundamentally affects the elderly, characterized by a progressive intellectual and personal decline, as well as a loss of memory , perception, reasoning, orientation and judgment.A characteristic of the disease is an observed decline in the function of cholinergic systems and, especially, an intense reduction of cholinergic neurons (ie neurons that release acetylcholine, which is believed to be a neurotransmitter involved in the mechanisms of learning and memory.) See Jones, I Tros, Intem. J. Neurosci., Vol. 50, p. 147 (1990); Perry Br. Med. Bull., Vol. 42, p. 63 (1986) and Sitara, et al., Science, Vol. 201, p, 274 (1978). It has been observed that nicotinic acetylcholine receptors, which bind to nicotine and other nicotinic agonists with high affinity, are depleted during the progression of SDTA. See Giacobini, J. Neurosci. Res., Vol, 27, p. 548 (1990); and Barón, Neurology, Vol. 36, p. 1490 (1986). As such, it would be desirable to provide therapeutic compounds that either directly activate the nicotinic receptors in place of the acetylcholine or act to minimize the loss of said nicotinic receptors. The cholinergic hypothesis (see Bartus, et al., Science, 217, 408, 1982) states that the enzyme choline acetyltransferase is depleted in the DSTA. This prevents the conversion of choline to acetylcholine. most of the postsynaptic receptors remain without deficiencies. The chemical substitution of acetylcholine, ie, nicotinic or uscarinic agonist, would be effective only if the receptor remained intact. Some attempts have been made to treat the DSTA. For example, it has been suggested that nicotine possesses the ability to activate nicotinic cholinergic receptors after acute administration, and predicts an increase in the number of such receptors after chronic administration to animals. See Rowell, Adv. Behav. biol., vol, 3, 1, p. 191 (1987); Marks, J. Pharmacol. Exp. Ther., Vol, 226, p. 817 (1983). It has also been proposed that nicotine can act directly causing the release of acetylcholine in brain tissue, improving cognitive functions and enhancing attention. See, Rowell, et al., J. Neurochem. , vol, 43, p. 1593 (1984); Sherwood, Human Psychophar. , vol. 8, pgs. 155-184 (1993); Hodges, and others, Bio. of Nic, Edit.by Lippiello, and others, p. 157 (1991); Sanakian, and others, Br. Jo. Psych., Vol, 154, p. 797 (1989); and the E.U.A. No. • • 4,965,074 to Leeson and 5,242,935 to Lippiello et al. Other methods for the treatment of the DSTA have been proposed, including those of the E.U.A. No. * - 5,211,188 to Caldwell et al., And 5,227,391 to Caldwell et al., And European Patent Application No. 588,917. Parkinson's disease (PD) is a debilitating neurodegenerative disease, currently of unknown etiology, characterized by tremors and muscular rigidity. A characteristic of the disease appears to involve the degeneration of dopaminergic neurons (ie, those that secrete dopamine). It has been observed that a symptom of the disease is a concomitant loss of nicotinic receptors that are associated with such dopaminergic neurons, and that is believed to modulate the process of dopamine secretion. See Rinne, et al., Brain Res., Vol. 54, p. 167-170 (1991) and Clark, et al., Br. J. Pharm., Vol. 85, pgs. 827-835 (1985). It has also been proposed that nicotine can relieve the symptoms of PD. See, Sith, et al., Rev. Neurisci., Vol, 3 (1), p. 25-43 (1982). Tourette syndrome (TS) is an autosomal dominant neuropsychiatric disorder characterized by a series of neurogenetic and behavioral symptoms. Typical symptoms include (i) the symptom of the disorder before age 21, (ii) multiple motor and phonic tics but not necessarily concurrent, (iii) training in the clinical phenomenology of tics, and (iv) occurrence of almost daily tics over a period exceeding one year. Motor tics usually include blinking of the eyes, cranial spasms, shrugging of shoulders and facial grimaces; while vocal or phonic tics include throat clearing, snorting, shouting, clicking of the tongue and pronouncing words out of context. The pathophysiology of ST is currently unknown, however, it is believed that a dysfunction in neurotransmission is involved in the disorder. See Calderón-González and others, Intem. Pediatr. vol. 8 (2), pgs. 176-188 (1993) and Oxford textbook of Medicine, Eds. Weatherall et al., Chapter 21.218 (1987). It has been proposed that the pharmacology of nicotine is beneficial in the suppression of symptoms associated with ST.

See Devor et al., The Lancet, Vol. 8670, p. 1046 (1989); Jarvik, Britisch J. of Addiction, Vol. 86, pgs. 571-575 (1991); McConville et al., Am. J. Psychiatry, Vol. 148 (6), p. 793-794 (1991); Newhouse et al., Brit. J. Addic. Vol. 86, pgs. 521-526 (1991); McConville et al., Biol. Psvchiatry, Vol. 31, you pay. 832-840 (1992); and Sanberg and another, Proceedings from Intl. Syrup.Nic .. S39 (1994). Attention deficit disorder (ADD) is a disorder that primarily affects children, although ADD can affect adolescents and adults. See Vinson, rch. Fam. Med., Vol. 3 (5), p. 445-451 (1994); Hechtman, J-_ Psychiatrv Neurosci .. vol 19 (3), p. 193-201 (1994); Faraone et al., Biol. Psychiatry., Vol 35 (6), p. 398-402 (1994) and Malone et al., J. Child Neurol. , vol. 9 (2), p. 181-189 (1994). Subjects suffering from the disorder usually have difficulty concentrating, listening, learning and completing tasks; and they are restless, nervous, impulsive and easily distracted. Attention deficit hyperactivity disorder (ADHD) includes the symptoms of ADD, as well as a high level of activity (for example, restlessness and movement). It has been described that the administration of nicotine to an individual improves the selective and sustained attention of the individual. See Warburton et al., Cholinergic control of cognitive resources, Neuropsychobiology, Ed. Mendelewicz, et al., Pp. 43-46 (1993). Schizophrenia is characterized by psychotic symptoms including illusions, catatonic behavior and remarkable hallucinations, and which finally leads to a deep decline in the psychosocial affect of the subject who suffers. It is believed that the neuroleptics used to treat schizophrenia are effective as a result of their interaction with the dopaminergic pathways of the CNS. In addition, a dopaminergic dysfunction associated with individuals suffering from schizophrenia has been proposed. See Lieberman and others, Schizophr. Bull. Vol. 19, pgs. 371-429 (1993) and Glassman, A er. J. Psvchiatry. Vol.150, pgs. 546-553 (1993). Nicotine has been proposed because of its efficacy in affecting the dysfunction in neurotransmitters associated with schizophrenia. See Merriam et al., Psychiatr. Annals. Vol. 23, pgs. 171-178 (1993) and Adler et al., Biol. Psychiatry, Vol. 32, pgs. 607-616 (1992). It has been proposed that nicotine has a series of pharmacological effects. Some of these effects may refer to effects on the release of neurotransmitters.

See, for example, Sjak-shie et al., Brain Res. Vol. 624, p. 295 * 298 (1993), where the neuroprotective effects of nicotine are proposed. The release of acetylcholine and dopamine by neurons following nicotine administration has been described by Rowell et al., J. Neuroche. , Vol. 43, p. 1593-1598 (1984); Rapier et al., J. Neurochem., Vol. 50, p. 1123-1130 (1988); Sandor et al., Brain Res. Vol. 567, p. 313-316 (1991) and Vizi. Br J. Pharmacol. Vol. 47, p. 765-777 (1973). The release of norepinephrine by neurons following nicotine administration has been described by Hall et al., Bioche. Pharmacol .. Vol. 21, pgs. 1829-1838 (1972). The release of serotonin by neurons following administration of nicotine has been described by Hery et al., Arch. Int, Pharacodyn. Ther .. Vol. 296, p. 91-97 (1977). The release of glutamate by neurons after administration of nicotine has been described by Toth et al., Neurochem. Res. Vol. 17, p. 265-271 (1992). Therefore, it would be desirable to provide a pharmaceutical composition containing an active ingredient possessing the pharmacology of nicotine, said pharmaceutical composition being capable of causing the release of the neurotransmitter in a subject in order to procure or treat a neurological disorder. In addition, nicotine is said to potentiate the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain disorders of the Central Nervous System (CNS). See, Sanberg, and others Pharmacol. Biochem. & Neurochem., Vol. 59, p. 48-54 (1993) and Hughes, Proceedings from Intl. Sy p. Nic, S40 (1994).

On the other hand, various beneficial pharmacological effects of nicotine have been proposed. See Decina et al., Biol.

Psychiatrv. Vol. 28, pgs. 502-508 (1990); Wagner et al., Pharmacopsychiat ry, Vol. 21, p. 301-303 (1988); Pomerleau et al., Addictive Behaviors, Vol. 9, p. 265 (1984); Onaivi et al., Life Sci., Vol. 54 (3), p. 193-202 (1994) and Hamon, Trends in Pharmacol, Res, vol. 15, pgs. 36-39. It would be desirable to provide a method useful for the prevention and treatment of a CNS disorder by administering a nicotinic compound to a patient susceptible to, or suffering from, said disorder. It would be very beneficial to provide the individuals suffering from a certain CNS disorder with an interruption of the symptoms of such diseases by administering a pharmaceutical composition having the pharmacology of nicotine and having a beneficial effect on the functioning of the CNS, but not produce any significant associated side effects (eg, increased heart rate blood pressure) that accompany the interaction of said compound with cardiovascular areas. It would be highly desirable to provide a pharmaceutical composition that incorporates a compound that interacts with nicotinic receptors that have the potential to affect CNS function, but does not significantly affect those receptors that have the potential to induce undesirable side effects (e.g. appreciable cardiovascular pressure and appreciable activity d skeletal muscles). Substances that can release pharmacologically significant amounts of nicotine to the central nervous system are among the most commonly known substances of abuse. These include, but are not limited to, tobacco cigarettes and "chewing tobacco" (see J. E. Henningfield, Ph.D. New England Journal of Med .. 1196, 1995). Cigarette smoking has been associated with an increased risk of lung cancer, emphysema and heart disease and an estimated 400,000 people will die in 1995 because of the combined effects of nicotine abuse in the United States (see JA Califano, Jr. New England Journal of Med., 1214, 1995). Nicotine is a strongly addictive drug, with 40% of those who tried tobacco becoming physically dependent later on. Attempts to abandon the use of nicotine, as in tobacco, have been ineffective, ending in failure more than 80% of attempts. Most attempts to quit fail in the first week due to the intense symptoms of withdrawal and strong desire. Effective therapy will avoid withdrawal symptoms, alleviate the strong desire and, simultaneously, antagonize the reinforcing effects of nicotine obtained from tobacco. Currently, few therapies are available to quit smoking and most involve replacing cigarettes with nicotine in the form of a patch or chewing gum. A high rate of relapse and a low overall success rate in quitting nicotine use is evidence of the need for additional and more effective therapies for the treatment of nicotine addiction than nicotine patch or gum. The pharmaceutical compositions used for the treatment of chronic nicotinism and nicotine addiction can be divided into two groups. The first covers the salts of silver, iron and copper. These substances are used to develop a negative reflex towards tobacco, usually in the form of a solution, or by incorporating in chewing gum compositions. The resulting reflex is based on the appearance of a very unpleasant taste in the mouth during the act of smoking after a preliminary rinsing of the oral cavity with saline solutions, or after using the chewing gum containing said salts (see Nasirov and others, "Anabasine Hycrochloride - New Antismoking Agent", Chemico -Pharmaceutical Journal, Vol. XII, 1978, No. 2, 149-152). The second group of agents used for the suppression of nicotine addiction comprises substances of an alkaloid nature, such as 1, 2, 3, 4, 5, 6-hexahydro-1,5-methano-pyrido [1] hydrochloride. , 2- a] [1, 5] diazocin-8-one (hereinafter cytisine), lobeline and anabasine, which have an effect on the H-colin-reactive systems of the organism similar to that of nicotine. The mechanism of its effect is due to its structural similarity to nicotine and the possible "competitive" antagonism between these alkaloids and nicotine (FF Khalikova, SH Nasirov., "On Pharmacology of the Alkaloid anabasine and some Ply eric and Copoly eric Derivates Thereof ", in Coil.," Pharmacology of Vegetable Compounds ", Proceedings of Tashkent University, 457, 1973, 1-16). U.S. Patent No. 4,971,079 discloses a composition comprising a biologically resorbable polymer containing a cation exchange group modified by an alkaloid of antinicotinic action, such as anabasine or cytisine, and a gum containing the same, without However, it has been found that the potency of cystisin is not elevated due to its inability to penetrate the brain barrier. (Reavill, C. et al., Behavioural and Phar acokinetic Studies On Nivotine, Cytisine and Lobeline, Neuropharmacology, 29, 619-624 (1990). Labadie LC (Peut-on supprimer les facteurs de risque in bronchopatie chronique et en particulier le tabac , Mediater, med., Me., 1976, 4, No. 112, 97, 99) describes the use of leaves of other Solanaceae plants, such as potato, tomato, eggplant and digitaline as tobacco substitutes. The most successful techniques to reduce the incidence of tobacco are based on nicotine-containing gum, which has been designed to reduce the symptoms of tobacco cessation.The declared success rate, although still relatively low, is approximately double to other procedures that have been used so far (See British Medical Journal, 286, (1983). The use of nicotine chewing gum has several problems that include its bad taste, destruction of the dental appliances and gastrointestinal discomfort, which reduces its use to suppress nicotine addiction. Furthermore, it has been found that nicotine-containing chewing gum does not fully satisfy the strong desire that most smokers experience for nicotine and, frequently, nicotine chewing gum becomes addictive for the patient. In the patent E.U.A. No. 4,284,089 a simulated simulative smoking device using a source of vaporizable nicotine is claimed. Although the cigarette itself is non-combustible, it releases a vapor containing nicotine that may not reach the level of nicotine in blood sufficient to satisfy a smoker. Thus, it has not been shown to satisfy the desire for nicotine level determined in blood to which many smokers have become accustomed, and even to which many smokers have become dependent. In addition, the simulated devices for simulative smoking of the type described in the patent E.U.A. No. 4,284,089 also have the bad taste of a substantial amount of nicotine introduced into the oral cavity. Most importantly, this nicotine does not enter the lungs to stimulate and provide the sensation that nicotine normally provides and to which the smoker has become accustomed. The current major therapy line for smoking cessation, as described in U.S. Patent No. 5,016,652, discloses a transdermal patch that is useful for the controlled release of nicotine in the user's bloodstream, thereby reducing the incidence of tobacco. Clinical trials have shown that abstinence rates (with the nicotine patch) can be achieved from 30 to 40% during the first six weeks of application (KJ Palmer, MM Buckley, D. Faulds, Drugs, 44 (3) 498-529 (1992) compared with 4 to 21% of a placebo, however, the long-term abstinence rates (more than 6 months) are considerably lower, being between 11 and 18%. a more effective therapy that provides a greater percentage of smokers who can quit smoking.

A pending application together with the present one (agent file number PC9582), assigned to the assignee of this application and incorporated herein by reference in its entirety, refers to heterocyclic compounds considered with pyridine which are useful in the treatment of addictive disorders such as the use of tobacco or other nicotine-containing products or in the treatment of neurobiological and mental disorders related to a decrease in cholinergic function. The pending application together with the present (file number of agent PC9728), assigned to the assignee of this application and incorporated herein by reference in its entirety, refers to 7-aza bicycloheptanes which are useful in the treatment of disorders Addictive drugs such as the use of tobacco or other nicotine-containing products or in the treatment of neuro-logical and mental disorders related to a decrease in cholinergic function. The pending application together with the present (agent's file number PC 9572), assigned to the assignee of this application and incorporated herein by reference, discloses certain compounds of (N- (pyridinyl ethylheterocyclic) ylidenamine as agents that bind to the nicotinic acetylcholine receptor.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a compound of formula where X is: a) -CH2NRIR2 R, Ri and R2 are independently selected from hydrogen and Ci-C alkyl; R3 is selected from hydrogen, halogen and Ci-Cs alkyl; 1 is an integer from 0 to 4; is an integer from 0 to 4; and n is an integer from 0 to 2; and the pharmaceutically acceptable salts thereof. Preferred compounds of Formula I are: [2- (6-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) ethyl] -dimethylamine; [2- (6-chloro-lH-pyrrolo [2,3-] pyridin-3-yl) ethyl] -methylamine; 3-pyrrolidin-2-ylmethyl-lH-pyrrolo [2,3-b] pyridine; 3- (1-methyl-pyrrol lidin-2-ylmethyl) -lH-pyrrolo [2,3-b] pyridine; dimethyl - [2- (lH-pi rrolo [2,3-b] pi ridin-3-yl) -ethyl] -a- ina; methyl- [2- (lH-pyrrolo [2,3-b] pyridin-3-yl) -ethyl] -amine; 2- (lH-pyrrolo [2,3-b] pyridin-3-yl-ethylamine; 3- (2-piperidin-l-yl-ethyl-lH-pyrrolo [2,3-b] pyridine.) In another aspect, this invention provides a method for treating a disease or condition of the brain associated with depletion of nicotinic receptors. in a patient in need thereof, comprising administering to said patient an effective amount of a compound of formula I above, or one of the pharmaceutically acceptable salts or prodrugs thereof In another aspect, this invention provides a pharmaceutical composition comprising a Composition of formula I and a pharmaceutically inert carrier The present invention further relates to all radioactively labeled forms of compounds of formula I comprising at least one radioactive label, preferably selected from 3H, "C and i- ^ C. radioactively labeled compounds are useful as research instruments and diagnosis in pharmacokinetic studies of metabolism and in blind tests in animals and humans. In addition, the present invention relates to pharmaceutical compositions for use in the reduction of nicotine addiction in a mammal comprising an amount of a compound of formula I, above, or one of the pharmaceutically acceptable salts or prodrugs thereof, effective to reduce nicotine addiction and a pharmaceutically acceptable vehicle. Yet another aspect of the present invention relates to compounds of formula I wherein said pharmaceutically acceptable acid addition salts are salts of acids selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, acid succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-toluoyl tartaric acid and mandelic acid. Another embodiment of the present invention relates to a method for treating addictive disorders and neurogenic or mental disorders in a mammal, comprising administering to said mammal an amount of compound of formula I effective in the treatment of said addictive disorders and said neurogenic disorders and mental DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention illustrated in formula I above are readily prepared from readily available starting materials. Substituted 1H-pyrrolo [2,3-b] pyridines are available from commercial suppliers or are known from the chemical literature, see, for example, (Synthesis, 1992, 7, 661-663); (Arch. Pharm., 1991, 324, 433-437); and (J. Am. Chem. Soc., 1955, 77, 457-459). In a general procedure illustrated below, a substituted lH-pi [2, 3-b] pi substituted with a substituted acid chloride such as chloroacetyl chloride is reacted in an inert reaction solvent and in p resence. of a catalysed acid, yielding 2-chloro-l- (lH-pi rrolo [2, 3-b] pi ri rin-3-yl) -ethanones.

Compound B is reduced to the corresponding chloroethyl compound, preferably with tri-ethylsilane in trifluoroacetic acid as solvent and the product is isolated by conventional procedures to provide compound (C) (B) (C) The conversion of the compound (C) to the corresponding amine derivative (compound D) is easily carried out by reaction with the selected amine in an inert reaction solvent and with an iodide catalyst. An alternative sequence is to prepare and isolate the intermediate iodine compound (D) and then convert the compound (E) to the appropriate amine.

In another aspect, [2m3-b] pi-rine-3-ca rbaldehydes are used as patertials for the compounds of the invention. Thus, the following compound (F) is reacted with an appropriate nitroester in the presence of ammonium acetate of an inert reaction solvent, yielding an alkene ester, the compound (G), which is further reacted with sodium borohydride, eliminating the double bond and forming the compound (H) (H) The compound (H) is then reduced with a suitable reducing agent such as Raney nickel and hydrogen to form the corresponding amine compound (I), which is converted into basic conditions in the cyclic amide (J).

The cyclic amide, the compound (J), is then reduced to the cyclic amine (K) with a strong reducing agent, for example, lithium aluminum hydride. The amine (K) can then be methylated in a two-step process to form the final compound (M). First, the t-butyl ester is prepared from compound (K) with di-tert-butyl dicarbonate foundering the amide (L). The reduction of (L) with lithium aluminum hydride p roporates the desired compound (M) of N-methyl amino cyclic.

The salts of the compound of formula I are prepared by treating the free base salts thereof with appropriate acids under general conditions known in the art. For example, these may be prepared by contacting the compound (group) of formula I with an appropriate acid, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent medium followed by filtration or by evaporation of the solvent, as is most appropriate, or, in the case of aqueous solutions, by lyophilization. Typical salts that can be prepared are hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-toluoyl acid tartaric acid and mandelic acid. The term "alkyl", as used herein, if not indicated otherwise, includes saturated monovalent hydrocarbon radicals with straight, branched or cyclic radicals, or combinations thereof. The compounds of formula I and their pharmaceutically acceptable salts (hereinafter "active compounds") can be administered orally, transdermally (e.g., by use of a patch., intranasal, sublingual, rectal, parenteral or topical. Transdermal and oral administration are preferred. It is most desirable that these compounds are administered in doses ranging from about 0.25 mg to about 1,500 mg per day, preferably from about 0.25 mg to about 300 mg per day in single or divided doses, although variations will necessarily be present. function of the weight and condition of the subject being treated and the particular route of administration chosen. However, it is most desirable to employ a dosage level in the range of about 0.02 mg to about 10 mg per kg of body weight. However, variations will occur depending on the weight and condition of the persons being treated and their individual responses to said medication, as well as the type of formulation chosen and the period and interval during which said administration is carried out. In some cases, dosing levels below the lower limit of the above-mentioned range may be more suitable, while in other cases even higher doses may be used, without causing any harmful side effects, provided that such larger doses are divided. first in several small doses for administration throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the various routes indicated above. More particularly, the active compounds can be administered in a variety of different dosage forms, for example, these can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, transdermal patches, tablets, dragees, hard candies, aerosol powders. , creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents. In addition, the oral pharmaceutical compositions can be sweetened and / or flavored appropriately. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing different excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, together with various disintegrants such as starch (preferably corn starch, potato or tapioca), alginic acid and certain complex silicates , together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, calcium lauryl sulfate and talc can be used for the preparation of tablets. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; including the preferred materials for this purpose are lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials and, if desired, emulsifying and / or suspending agents, together with diluents such as water, ethanol , propylene glycol, glycerol and various combinations thereof. For parenteral administration, a solution of an active compound in sesame or peanut oil or an aqueous propylene glycol can be used. The aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical practices well known to those skilled in the art. It is also possible to administer the active compounds topically when treating inflammatory disorders of the skin and this can be done by means of creams, jellies, gels, pastes, ointments and the like, in accordance with conventional pharmaceutical practice.

BIOLOGICAL ASSAY The efficacy of the active compounds in the suppression of nicotine binding to their specific receptor sites is determined by the following procedure which is a modification of the Lippiello, P.M. and Fernández, K.G. (in "The Bindings of L- [3 H] Nicotine To a Single Class of High-Affinity Sites in Rat Brain Membranes", Molecular Pharm., 29, 488-54, (1986) and Anderson, DJ and Arneric, SP ( in "Nicotinic Receptor Binding of 3H-Cystisine, 3H-Nicotine and 3H-Methylcarbamylcholine in Rat Brain", European J. Pharm., 253, 261-67 (1994).

PROCESS Male Sprague-Dawley rats (200-300 g) from Charles River were housed in groups of suspended wire cages and kept in a 12 hour light / dark cycle (7 a.m. -7 p.m. light period). They received conventional Purina Rat Chow food and water ad libitum. The rats were sacrificed by decapitation. Cerebels were removed immediately after sacrifice. The membranes were prepared from brain tissue according to the procedures of Lippiello and Fernandez (Molec. Pharmacol., 29, 448-454 (1986) with some modifications, whole brains were extracted, rinsed with ice-cold buffer and homogenized with 0 ° C in 10 volumes of buffer (weight / volume) using a Brinkmann Polytron ™, in position 6 for 30 seconds The buffer was composed of 50 mM Tris HCl and had a pH of 7.5 at room temperature. sedimented by centrifugation (10 minutes, 50,000 xg, 0 to 4 ° C) The supernatant was discarded and the membranes were gently resuspended in the Polytron and centrifuged again (10 minutes, 50,000 xg, 0 to 4 ° C). the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.0 g / 100 ml, the composition of the conventional assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM KC1, 2 M MgCl2, CaCl2 my had a pH of 7.4 at temperat ura environment Routine tests were carried out on borosilicate glass test tubes. The assay mixture was usually comprised of 0.9 mg of membrane protein in a final incubation volume of 1.0 ml. Three sets of tubes were prepared in which the tubes of each set contained 50ml of vehicle, blank, or solution of the test compound, respectively. 200 ml of [3H] -nicotine in assay buffer was added to each tube, followed by 750 ml of membrane suspension. The final concentration of nicotine in each tube was 0.9 nM. The final concentration of cytisine in the blank was 1 mM. The vehicle consists of deionized water containing 30 ml of IN acetic acid per 50 ml of water. The test compounds and cytisine were dissolved in vehicle. The tests were started by vortexing after the addition of the membrane suspension to the tube. Samples were incubated from 0 ° C to 4 ° C in a rapid vacuum agitation bath through What an GF / B ™ glass fiber filters using a multi-manifold Brandel ™ tissue harvester. After the initial filtration of the test mixture, the filters were washed twice with ice-cold assay buffer (5 ml each). The filters were placed in counting vials and mixed vigorously with 20 ml of Ready Safe ™ (Beckman) before determining the radioactivity. The counting of the samples was performed in a LKB Wallach Rackbeta ™ liquid scintillation counter at an efficiency of 40-50%. All determinations were made in triplicate.

C LCULOS The specific binding, IX, to the membrane is the difference between the total binding in the samples that contain only vehicle and the membrane, VII, and the non-specific binding in the samples that contain the membrane and cytisine, VIII, that is, Union specific = IX = VII - VIII. The specific binding in the presence of test compound, XI, is the difference between the total binding in the presence of test compound, X, the non-specific binding, VIII, ie, XI = X-VIII. % inhibition = (1 - (XI / IX) 100 The compounds of the invention, which were tested, showed CIso values less than 2 μM.

EXAMPLE 1 2-Chloro-l- (6-ClQP? -lH-pyrrolo [2,3-b3pyridin-3-yl) -ethanone.

To a solution of 400 mg (2.62 M) of 6-chloro-lH-pi rrolo [2,3-b] pyridine (Synthesis, 1992,7, 661-663) dissolved in 15 ml of carbon disulfide were added. 2.62 g of anhydrous aluminum chloride and 0.229 ml (2.88 mM) of chloromethyl acetyl chloride. The reaction was refluxed for 2 hours. A second equivalent of chloromethyl acetyl chloride was added to the reaction and the reflux was continued for a further 1 hour. The reaction mixture was cooled to room temperature and decanted and discarded the carbon disulfide solvent. The residue was cooled (ice bath) and the excess aluminum chloride was decomposed by slow addition of water, the resulting mixture was mixed with an equal volume of ethyl acetate and the pH adjusted to 9.0 (Na 3). . This mixture was filtered and the ethyl acetate layer was separated from the aqueous layer. The ethyl acetate layer was dried and evaporated. The residue was triturated with methyl isobutyl ketone and filtered to give 200 mg of product. NMR (DMSO-de) d 12.82 (s, 1H), 8.62 (s, 1H), 8.5 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8) , 5 Hz.lH), 4.92 (s, 2H). mass spectrum m / z = 229, 231 (P + l; P + 3). Rf (CH2Cl2: CH32? H 10: 1) = 0.8.

EXAMPLE 2 l- (6-Chloro-lH-pyrrolo [2.3-] pyridin-3-yl) -2-dimethylaminoethanone.

The title compound was prepared from 6-chloro-lH-pyrrolo [2,3-] pyridine (Synthesis, 1992, 7, 661-663) and dimethylaminoacetyl chloride hydrochloride (Arch. Pharm., 1991, 324, 433-437) in a procedure similar to Example 1. NMR (DMS0-d6 d 12.65 (s, 1H), 8.60 (s, 1H), 7.95 (d, 1H), 7.32 (d , 1H), 3.60 (s, 2H), 2.22 (s, 3H). ^ C NMR (DMSO-Dβ) 195.6, 147.5, 144.4, 134.8, 132.7, 118 , 0, 116.8, 114.0, 65.9, 45.2 (2). Mass spectrum: 237, 239 (P + l, P + 3).

EXAMPLE 3 6-Chloro-3- (2-chloro-ethyl) -lH-pyrrolo [2.3-b] pyrazole.

To a solution of 400 mg of 2-chloro-l- (6-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -ethanone (1.75 mM) in 2.80 ml of trifluoroacetic acid 1.8 ml (12 M triethylsilane was added and the mixture was stirred at room temperature for 48 hours.) The reaction mixture was diluted with 20 ml of ethyl acetate and the pH was adjusted to 8.0 with the addition of NaHCO 3. The ethyl acetate layer was separated from the water layer, dried (MgSO-i) and evaporated to yield 400 mg of a yellow solid residue.This residue was chromatographed on 25 g of silica using hexanes: acetate 1: 1 as eluent The appropriate fractions were combined to give 350 mg of 6-chloro-3- (2-chloro-ethyl) -lH-pyrrolo [2,3-b] pi-ridine as a white solid.1 NMR (CDCl3) d 11.35 (s, 1H), 7.88 (d, J = 8 Hz, 1H), 7.40 (s, 1H), 7.10 (d, J = 8 Hz, 1H), 3.75 (t, J = 6H, 2H), 3.2 (t, J = 6 Hz, 2H). 13C NMR (CDCl3) 147, 129, 123, 118, 155, 111, 44, 29. Mass spectrum: m / e = 216, 218 (p + l, p + 3).

EXAMPLE 4 [2- (6-Chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -ethyl] dimethylamine.

To a saturated solution of 25 ml of dimethylamine in ethanol were added 110 mg (0.51 mM) of 6-chloro-3- (2-chloro-ethyl) -lH-pyrrolo [2,3-b] pyridine and 76 mg (0.506 mM) of sodium iodide. The mixture was heated to 900C in a steel autoclave for 2 hours. After cooling to room temperature, an additional 15 ml of ethanol saturated with dimethylamine was added and the autoclave was heated at 90 ° C for 14 hours. The reaction mixture was cooled to room temperature and the ethanol was evaporated. The residue was mixed with 25 ml of water, the pH was adjusted to 9 and the mixture was extracted with ethyl acetate. The ethyl acetate was dried and evaporated giving 115 mg of an oil. The oil was triturated with hexanes to give a white solid. NMR (CDCl 3) d 10.37 (s, 1H), 7.85 (d, 1H), 7.16 (s, 1H), 7.05 (d, 1H), 2.95 (t, 2H), 2.62 (t, 2H, 2.32 (s, 6H). 3C NMR (CDCl 3 147.9, 143.7, 129.7, 122.7, 118.9, 114.9, 133.0, 60.1, 45.5 (2), 23.9 Mass spectrum: m / e = 224, 226 (P + l, P = 3) The above material was dissolved in 10 ml of ethyl acetate and Reacted with 10 ml of ethyl acetate saturated with HCl, The resulting precipitate was filtered and dried to give [2- (6-chloro-lH-pyrrolo [2,3-b] pi-ridin-3-yl) -dimethyl ester hydrochloride. -amine EXAMPLE 5 6-Chloro-3- (2-iodo-ethyl) -lH-pyrrolo [2,3-b3pyridine.

A mixture of 800 mg (3.72 mM) of 6-chloro-3- (2-chloro-ethyl) -lH-pyrrolo [2,3-b] pyridine was refluxed in 150 ml of acetone for 12 hours and 1.67 g (11.2 M) of Nal. The reaction mixture was cooled to room temperature and the acetone was evaporated. The residue was treated with saturated sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extractors were combined, dried with a2SO4 and evaporated to yield 1.0 g of a pale yellow solid. This solid (approximately 80% of 6-chloro-3- (2-iodo-ethyl) -lH-pyrrolo [2, 3-b] pi ridine and 20% of 6-chloro-3- (2-chloro- ethyl) -lH-pyrrolo [2,3, b] pyridine) was used in subsequent reactions without further purification. NMR (CDCl 3) d 11.3 (s, 1H), 7.8 (d, 1H), 7.2 (s, 1H), 7.1 (d, 1H), 3.42 (t, 2H, 3.35 (t, 2H). 307.309 (P = 1, P + 3).

EXAMPLE 6 [2- (6-Clo? -o-lH-pyrroloC2,3-b] pyridin-3-yl) -ethyl] roethylamine.

A mixture of 1 g (3.26 mM) of 6-chloro-3- (2-iodo-ethyl) -lH-pyrrolo [2,3-b] pyridine and 0.49 g (3.2 mM) was mixed. of Nal in 100 ml of an ethanol solution saturated with methylane aegas. This solution was heated to 100 ° C in a steel autoclave for 12 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was subjected to chromatography on silica using a mixture of CH2Cl2: CH30H 10: 1 as eluent. The appropriate fractions were combined and evaporated. The residue was crystallized from isopropyl ether-ethanol to give 140 mg of [2- (6-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -ethyl] methylamine. P.F. = 214-215 ° C.

NMR (DMSO-dβ) d 11.75 (s, 1H), 8.08 (d, 1H), 7.41 (s, 1H), 7.15 (d, 1H), 3.20 (t, 2H) ), 3.02 (t, 2H), 2.60 (s, 3H). 13 C NMR (DMSO-dβ) 147.5, 143.2, 129.9, 124.8, 118.2, 114.8, 108.7, 48.4, 32.6, 21.6. Mass spectrum: m / e = 210, 212 (P + l, P + 3).

EXAMPLE 7 4-Nitro-5- (lH-pyrrolo [2,3-b] pyridin-3-i1) -pent-4-enoic acid methyl ester.

A mixture of 1.47 g (10 mM) of lH-pi rrolo [2,3-b] pyridine-3-carbaldehyde (J. Am. Chem. Soc, 1955) was refluxed in 10 ml of THF for 1 hour. , 77, 457-459), 77 mg (10 M) of ammonium acetate and 2.55 ml (20 mM) of methyl 4-nitrobutyrate (Aldrich). An additional 500 mg of ammonium acetate was added and the mixture was refluxed for a further 3 hours.

The reaction was cooled to room temperature, the solvent was evaporated and the residue chromatographed on silica using ethyl acetate as eluent. The appropriate fractions were combined to provide 410 mg of the desired product as an oil. NMR (DMSO-dβ) d 12.80 (s, 1H), 8.42 (2, 1H), 8.37 (m, 2H), 8.18 (s, 1H), 7.25 (m, 1H), 3.62 (s, 3H), 3.25 (t, 2H), 2, 68 (t, 2H). 13 C NMR (DMSO-dβ) 172.4, 148.7, 144.5, 144.4, 130.0, 127.3, 126.9, 119.9, 117.3, 106.1, 54, 6, 30.5, 23.6. Mass spectrum: m / e = 276 (P + l).

EXAMPLE 8 Methyl ester of the acid-nitro-5-ClH-pyrrolo [2.3-b + pyridin-3-i1) -pentanoic acid.

To a suspension of 0.124 g (0.45 mM) of 4-nitro-5- (lH-pyrrolo [2,3-b] pyridin-3-yl) -pent-4-enoic acid methyl ester in 8 ml of methanol was added 125 mg (3.3 M) of sodium borohydride. The reaction mixture was stirred at room temperature for 1 hour. An additional 100 mg of sodium borohydride was added and the mixture was stirred for an additional hour. To this mixture was added 1 ml of acetic acid. The reaction solvent was evaporated and the residue was dissolved in ethyl acetate and treated with saturated sodium bicarbonate. The ethyl acetate layer was separated from the aqueous layer, dried and evaporated to yield 130 mg of product. TLC (CHCl3: CH30H 10: 1) Rf = 0.35. NMR (CDC13) d 11.8 (s, 1H), 8.35 (d, 1H), 7.90 (d 1H), 7.25 (s 1H), 7.10 (dd, 1H), 490 ( m, 1H), 3.65 (s, 3H), 3.45 (dd, 1H), 3.20 (dd, 1H), 2.1-2.5 (, 4H). NMR of I? (CDCl 3 172.3, 148.8, 142.6, 127.0, 124.2, 119.8, 115.7, 107.6, 80.0, 51.9, 30.2, 29.9, 28.3 Mass spectrum: m / e = 278 s (P + l).

EXAMPLE 9 This methyl 4-amino-5- (lH-pi rrolo acid [2,3-b3pi ridin-3-D-pentanoic acid methyl ester.

To a solution of 165 mg (0, 595 mM) of 4-nitro-5- (lH-pyrrolo [2,3, b] pyridin-3-yl) -pentanoic acid methyl ester in 15 ml of acetic acid were added 450 mg (0.595 mM) of acetate ammonium and approximately 100 mg of Raney nickel. The mixture was hydrogenated at 3.45 x 10 Pa for 12 hours, the mixture was filtered and the solvent was evaporated. The residue was treated with an equal volume of ethyl acetate and saturated sodium bicarbonate. The ethyl acetate layer was dried and evaporated to give 85 mg of product which was used in the next synthesis step without further purification. TLC: (CHCl3: CH30H 10: 1) Rf = 0, 1. Mass spectrum: m / e = 248 (P + l).

EXAMPLE 10 5-ClH-Pi rrolo [2.3-b] pi ridin-3-ylmethyl) -pi rpolidin-2-one.

A solution of 2.5 g (0.101 mM) of 4-amino-5- (lH-C2,3-b] pyridin-3-yl) -pentanoic acid methyl ester was dissolved in 20 ml of ethyl acetate. solution was added 20 ml of IN sodium carbonate and the mixture was stirred at room temperature for 6 hours. The ethyl acetate layer was dried and evaporated. The residue was chromatographed on silica using CHCl3: CH30H 95: 5 affording 1.48 g of product as a white crystalline solid. P. F = 160-162 ° C. NMR (CDCl 3) d 11.4 (s, 1H), 8.05 (m, 1H), 7.85 (d, 1H), 7.45 (s, 1H), 7.18 (s, 1H), 6.95 (m, 1H), 4.0 (m, 1H), 2.8-3.0 (m, 2H), 2.2-2.4 (m, 3H), 1.85 (m, 1 HOUR). 13 C NMR (CDCl 3) 178.6, 148.9, 142.4, 127.0, 123.6, 120.1, 115.3, 109.8, 55.2, 32.6, 30.3, 26.8.

EXAMPLE 11 3-Pyrrolidin-2-ylmethyl-lH-pyrrolo [2.3-b] pi ridine.

A mixture of 313 mg (1.46 mM) of 5- (lH-pyrroloC2,3-b] pyridin-3-ylmethyl) -pyrrolidin-2-one and 170 mg was refluxed in 10 ml of dioxane for 5 hours. (4.47 mM) of lithium aluminum hydride, the solution was cooled to room temperature and the excess of lithium aluminum hydride was decomposed with 1 ml of saturated NaCl. To this mixture were added 300 ml of ethyl acetate and 15 g of anhydrous Na 2 SO. The reaction mixture was filtered and evaporated giving 254 mg of the amine as a dark oil. This material was used in the next synthesis stage directly. Mass spectrum: m / e = 202 (p = l).

EXAMPLE 12 2- (lH-Pyrrolo [2m3.b] pyridin-3-ylmethyl) -pyrrolidine-l-carboxylic acid tert-butyl ester.

A mixture of 254 mg (1.26 mM) of 3-pyrrolidin-2-ylmethyl-1H-pyrrolo [2,3-b] pyridine and 302 mg (1.38 M) of dicarbonate was stirred at room temperature for 12 hours. of di-tert-butyl (Aldrich) in 10 ml of dioxane. TLC (CHCl3: CH30H 10: 1) indicated formation of new product and the mass spectrum indicated m / e = 302 (p + l). This solution was used directly in the next synthesis stage.

EXAMPLE 13 3- (l-Methyl-PyrrOlidin-2-ylmethyl) -lH-pyrrolo [2.3-b3pi Ridine. 177 mg (4.65 mM) of lithium aluminum hydride was added to the above dioxane solution. The mixture was refluxed for 6 hours. The reaction mixture was cooled to room temperature and the excess lithium aluminum hydride was decomposed by the addition of 1 ml of saturated NaCl. The mixture was poured into 300 ml of ethyl acetate and the solution was dried with 20 g of anhydrous NaSO 4. The mixture was filtered and evaporated. The residue was subjected to chromatography on 10 g of deactivated silica (500 g of silica suspended in 2 1 of KH2PO-, 4% for 1 hour, and dried at 120 ° C), yielding 125 mg of product as an oil. NMR (CDCl 3) d 11.4 (s, 1H), 7.95 (d, 1H), 7.18 (s, 1H), 7.08 (, 1H), 3.15 (m, 2H), 2 , 6 (m, 1H, 2.45 (s, 3H), 2.43 (, 1H), 2.20 (m, 1H), 1.8 (m, 2H), 1.6 (m, 2H). 13 C NMR (CDCl 3) 149.1, 142.3, 127.4, 122.8, 120.6, 115.1, 112.3, 66.8, 57.5, 40.8, 31.4, 30.1, 21.8. Mass spectrum: m / e = 216 (p + l). TLC (CHC13: CH30H 10: 1): Rf = 0, 1.

EXAMPLE 14 J. Het. Chem .. 1984. 21. 421-3 3- (2-Yodo-ethyl) -lH-pyrrolo í 2.3-b] pi ridine To a solution of 7.0 g (38.8 mM) of 3- (2-chloro-ethyl) -lH-pyrrolo [2, 3-b] pi ridine in 250 ml of acetone was added 17.5 g (116 g). mM) of Nal and the mixture was heated at reflux for 48 hours. The reaction was cooled to room temperature, filtered and the solvent was evaporated. The residue was dissolved in 100 ml of ethyl acetate and water, and the pH was adjusted to 10 with IN NaOH. The ethyl acetate layer was dried and evaporated giving 10.1 g of product as a yellow solid. NMR (CDCl3) d 11.6 (s, 1H), 8.32 (d, 1H), 7.92 (d, 1H), 7.29 (s, 1H), 7.08 (m, 1H), 3.40 (m, 2H), 3.32 (m, 1H). 13 C NMR (CDCl 3) 149, 142.5, 127.1, 123.0, 119.7, 115.4, 113.6, 30.3, 5.8. Mass spectrum: m / e = 273 (p + l).

EXAMPLE 15 Dimethyl-] 2- (lH-pyrrolo [2.3.b] pyridin-3-yl) ethyl-3-amine.

A solution of 544 mg (2.0 mM) of 3- (2-iodo-ethyl) -lH-pyrrolo [2,3-b] pi-ridine was dissolved in 100 ml of ethanol which had been saturated with dimethylamine gas. This solution was placed in a steel autoclave and heated at 100 ° C for 3 hours. The reaction was cooled to room temperature and the solvent was evaporated giving 300 mg of product as a yellow amorphous solid. NMR (CDCl 3) d 11, 9 (s, 1H), 8.28 (d, 1H), 7.90 (d, 1H9, 7.15 (s, 1H), 7.02 (m, 1H), 2.92 (t, 2H ), 2.60 (t, 2H), 2.30 (s, 6H), 13 C NMR (CDCl 3) 149.2, 142.1, 127.2, 122.6, 120.3, 114.9, 112.3, 60.3, 45.4 (2), 42.3, 23.9 Mass spectrum: m / e = 190 (p + l).

EXAMPLE 16 Methyl- [2- (lH-pyrrolo [2,3-b] pyridin-3-yl) -ethyl] -amine.

This was prepared as described in the previous example using a saturated solution of ethanol with methylamine gas. NMR (CDC13) d 11.3 (s, 2H), 8.3 (, 1H), 7.9 (d, 1H), 7.15 (s, 1H), 7.0 (m, 1H), 2 , 9 (m, 4H), 2.42 (s, 3H). 13 C NMR (CDCl 3) 149.2, 142.4, 127.3, 122.8, 120.2, 115.1, 112.2, 52.1, 36.3, 25.7. Mass spectrum: m / e = 176 (p + l).

EXAMPLE 17 2- (lH-PyrroloC2m3.b3pyridin-3-yl) -ethylamine.

This was prepared as described in the previous example using a saturated solution of ethanol with ammonia.

Mass spectrum: m / e = 162 (p + l). This compound is a known compound (J.Am.Chem. Soc, 1956, 78, 1247, Patent E.U.A. No. 3,362,956.

EXAMPLE 18 3- (2-Piperidin-1-yl-ethyl) -lH-pyrrolo [2,3-b3pi ridine.

Reflux solution was maintained for 12 hours 100 g (0.37) mM) of 3- (2-iodo-ethyl) -lH-pi rrolo [2, 3, -b] pi ridine and 0.1 ml (1.0 mM) of piperidine in 1, 0 ml of ethanol. The reaction was cooled to room temperature and added to 50 ml of a mixture of ethyl acetate and water. The pH was adjusted to 9.0 with IN NaOH and the ethyl acetate layer was dried and evaporated, yielding 80 mg of product as a yellow solid. NMR (CDC13) d 10.9 (s, 1H), 8.3 (d, 1H), 7.9 (d, 1H), 7.15 (s, 1H), 7.0 (m, 1H), 2.9 (t, 2H), 2.6 (t, 2H), 2.5 (m, 4H), 1.7 (m, 4H), 1.4 (m, 2H). 13 C NMR (CDCl 3) 149.2, 142.4, 127.3, 122.2, 120.3, 115.1, 112.9, 60.0, 54.6 (2), 25.9 (2 ), 23.0. Mass spectrum: m / e = 230 (p + l).

Claims (11)

NOVELTY OF THE INVENTION
2. A compound of formula where X is: a) -CH2NRIR2
3. R, R1 and R2 are independently selected from hydrogen and Ci-C alkyl; R3 is selected from hydrogen, halogen and Ci-C alkyl; 1 is an integer from 0 to 4; m is an integer from 0 to 4; and n is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, wherein X is -CH2NRIR2. 3. Compound according to claim 1, wherein X is
4. 4. - Compound according to claim 1, wherein X is
5. 5. - Compound according to claim 2, wherein R3 is 6-chloro.
6. 6. The compound according to claim 3, wherein R3 is 6-chloro.
7. 7. The compound according to claim 4, wherein R3 is 6-chloro.
8. 8. Compound according to claim 1, selected from the group consisting of: [2- (6-chloro-lH-pyrrolo [2,3-b Dpi ridin-3-yl) ethyl] -dimethylamine; [2- (6-chloro-lH-pi rrolo [2,3-b] pyridin-3-yl) ethyl] -methyl-lal; 3-pi rrolidin-2-ylmethyl-1H-pi rolo [2, 3-b Dpi ridine; 3- (1-methyl-pyrrolidin-2-ylmethyl) -lH-pyrroloC 2, 3-b Dpi-ridine; dimethyl L-C2- (lH-pi rrolo [2,3-bDpyridin-3-yl) -ethyl D -amine; methyl- [2- (lH-pi rolo [2, 3-b Dpi ridin-3-yl) -ethyl D-amine; 2- (lH-pi rrolo [2,3-bDpi ridin-3-yl-ethylamine; and 3- (2-piperidin-l-yl-ethyl-lH-pi rrolo [2, 3-bDpi ridine. The use of an effective amount of the compound according to claim 1, for preparing a composition for treating a disease or disorder of the brain associated with a depletion of nicotinic receptors in a patient in need thereof 10. The use according to claim 9, wherein said brain disorder is addicted to nicotine 11. Pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically inert carrier.