UA68347C2 - Derivatives of 8-azabicyclo[3.2.1]oct-2-ene and octane, their synthesis and use - 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, ÄcF3, 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, ÄcF3, 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, ÄcF3, 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. (1), (a).

Description

Description of the invention

The invention relates to new derivatives of 8-azabicyclo|3,2,|oct-2-ene and -octane, which are cholinergic ligands 2 on nicotinic AC receptors. The compounds of the invention may be used to treat conditions or disorders of the cholinergic system of the central nervous system, pain, inflammatory diseases, diseases caused by smooth muscle contraction, and may also aid in the cessation of chemical drug abuse.

Endogenous cholinergic neurotransmitter, acetylcholine, exerts its biological effect through cholinergic 70 receptors of two types: muscarinic receptors of AC and nicotinic receptors of AC. Muscarinic AC receptors have been found to quantitatively dominate AC nicotinic receptors in a brain area important for memory and cognition, and therefore much research aimed at finding agents for the treatment of memory disorders has been devoted to the synthesis of muscarinic AC receptor modulators. Recently, however, there has been interest in the development of nicotinic ASI receptors. Several 19 diseases are associated with the degeneration of the cholinergic system, namely, Alzheimer's disease, vascular dementia, and cognitive impairment caused by organic brain damage of alcoholic origin. Indeed, some disorders of the central nervous system can be caused by cholinergic, dopaminergic, adrenergic or serotonergic insufficiency. Alzheimer's disease is characterized by profound memory loss and cognitive impairment caused by a significant decrease in the number of cholinergic neurons, such as those that release acetylcholine. With the development of Alzheimer's disease, the number of nicotinic receptors in AS also decreases.

It is believed that cortical neurons in Alzheimer's disease die due to a lack of stimulation by nicotinic receptors. It can be hoped that treatment of such patients with modulators of the nicotinic receptor ASP will not only improve the patient's memory, but will support the viability of these neurons. Smoking appears to protect an individual from neurodegeneration, and it is likely that other compounds that act on this receptor in a similar way also have neuroprotective effects. Gee)

However, degeneration of the cholinergic system does not only occur in patients suffering from the disease

Alzheimer's disease, but are found in healthy adults and elderly rats. Therefore, it can be assumed that the cholinergic system participates and is partially responsible for memory impairment in animals and elderly people. Therefore, a nicotinic receptor modulator can be used to treat Alzheimer's disease, memory loss, memory disorders, dementia caused by AIDS, senile dementia, or “Her neurodegenerative disorders.

It is believed that Parkinson's disease is associated with the degeneration of dophanergic neurons. One of the symptoms of this disease is the loss of nicotinic receptors associated with dopaminergic neurons, and possibly impaired dopamine release. Because long-term administration of nicotine increases the number of receptors, the administration of nicotinic receptor modulators can reduce the symptoms of Parkinson's disease. Other conditions and disorders or diseases caused by deficiencies in the dopaminergic system include drug addiction, depression, obesity, and narcolepsy.

Tourette syndrome is a disorder with many neurological and behavioral symptoms. "

It is believed that its cause is neurotransmitter dysfunction, although the pathophysiology is not yet known, and treatment with nicotine gives a positive effect (Oemog ei ai., Te I apsei, mo!. 8670, p. 1046, 1989). c Schizophrenia is a severe psychiatric disease. For treatment, neuroleptics are used, the action of which

With" is explained by interaction with the dopaminergic system. Nicotine treatment of schizophrenia is proposed (Megtiat ei ai.,, Rgzuspiaig. appaiiv, my. 23, p. 171-178, 1993; Adieg ei a/!., Visi. Rzuspiaigu, moI. 32, p. 607-616, 1992) .

Effects of nicotine on neurotransmitter release in several systems have been reported. There were reports of the release of acetylcholine and dopamine after nicotine administration (). Meyhospet., mo!.43, b 1593-1598, 1984), on the release of norepinephrine (nai ei a!., Viospet. Rpagtasoi., moI.21, 1829-1838, 1084),

Ge | on the release of serotonin (Negu ei ai., Agsy. Ipii. Ripagtasodip. Tpep, moI.296, p.91-97, 1977), the release of glutamate (Toii ei aiI., Mephospet. Kezv., moI.17, p.265 -271, 1992). o It is believed that the serotonin system and its dysfunctions are the cause of such diseases, conditions or disorders as anxiety, depression, eating disorders, obsessive compulsive disorder, panic disorder, drug abuse, alcoholism, pain, memory impairment 'yati, pseudo feeble-mindedness, Hanser's syndrome, migraine, tm bulimia, obesity, premenstrual syndrome or late luteal phase syndrome, tobacco abuse, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, difficult erection, apogechia peghosis, sleep disorders, autism, mutism or trichocryptomania. 29 Nicotine improves concentration and the ability to solve problems. Therefore, we can hope that the compounds are capable

HF) modulate the nicotinic receptor, may be useful in the treatment of learning disabilities, recognition deficits, attention deficit hyperactivity disorder, and dyslexia.

Tobacco use, and especially cigarette smoking, is considered a serious threat to health. However, the nicotine withdrawal symptoms that result from smoking cessation make it difficult to kick the habit. These 60 symptoms include irritability, anxiety, difficulty concentrating, restlessness, increased heart rate, increased appetite, and weight gain. Nicotine has been shown to alleviate these symptoms.

Withdrawal from addictive drugs, such as opiates, benzodiazepines, ethanol, tobacco, or nicotine, is a painful process characterized by anxiety and frustration. Nicotine has been found to reduce anxiety, irritability, frustration, and feelings of tension without producing reactive depression, 62 drowsiness, or sedation, and compounds similar in characteristics to nicotine are thought to have similar effects.

Mild to moderate pain is usually treated with nonsteroidal anti-inflammatory drugs, and opiates are used for severe pain. Opiates have well-known adverse effects, including chemical dependence and potential abuse, as well as respiratory and gastrointestinal depression. Therefore, there is an urgent need for analgesic compounds that do not have such side effects and can relieve mild, moderate, and severe pain of an acute, chronic, or recurrent nature, as well as migraine, postoperative pain, and phantom limb pain.

Epibatidine, a compound derived from the skin of a poison dart frog, is a very powerful pain reliever, approximately 500 times more potent than morphine. The analgesic effect is not affected by naloxone, which indicates a slight affinity for opiate receptors. Epibatidine is an agonist of the nicotinic cholinergic receptor and it is highly likely that compounds with the same ability to modulate the receptor may produce a strong analgesic response. It has been demonstrated that the compounds of the invention can be used to modulate smooth muscle contractions and, therefore, to treat or prevent conditions, disorders or diseases caused by smooth muscle contractions, e.g., convulsions, adiposis, premature labor, diarrhea, asthma, epilepsy, slow dyskinesia, 7/5 piperkinesis.

Nicotine is known to affect appetite and it is hoped that AMP nicotinic receptor modulators may be used as appetite suppressants in the treatment of obesity and eating disorders.

Cholinergic receptors play an important role in the functioning of muscles, organs and, in general, in the central nervous system. There is a complex interaction between cholinergic receptors and the function of receptors of other neurotransmitters, for example, dopamine, serotonin and norepinephrine.

Nicotinic receptor modulator compounds may be useful in the prevention or treatment of conditions or disorders such as inflammation, skin inflammation, Crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea, neurodegeneration, peripheral neuropathy, amyotrophic lateral sclerosis, nociception, endocrine disorders , thyrotoxicosis, pheochromocytoma, hypertension, arrhythmia, sch 2g5 manic-depressive state, Huntington's disease, consequences of time shift during long-distance air travel.

Compounds according to the invention are nicotinic receptor modulators and exhibit nicotinic pharmacology, i) preferably without side effects associated with nicotine as such. In addition, it is hoped that these compounds are able to enhance the secretion of neurotransmitters and suppress the symptoms associated with low neurotransmitter activity. Structurally similar analogues of the compounds according to the invention are described in EP 122580, namely, pyrimidine derivatives -

Dihydrofolate reductase inhibitors suitable for the treatment of bacterial infections and malaria. -

OV 2298647 describes bridging piperidines - growth hormone release promoters. In UMO 97/13770 it is described (Inhibitors of monoamine neurotransmitter reuptake. In EP 0498331 it is described

M-(aryloxyalkyl)-heteroaryl-8-azabicyclo(3.2.1)octanes as antipsychotic agents and inhibitors of repeated so

C5 absorption of serotonin. In U. Med. Spet., 1995, 38, 1998-2008 described Cs-ligands capable of anxiolytic action. At 9. Oh. Spet., 1994, 59, 2164-2171 described representatives of shortened ibogaines.

Therefore, there is a great need to create modulators of the nicotinic receptor ASP with more favorable pharmacological properties, that is, such as, for example: high selectivity of binding subtypes of the neuronal pASNK receptor, for example, subtype A?7, low affinity to m ulcerative subtype, and promotion of cell survival, "" efficiency of attention stimulation during oral administration of ip mimo (rat model), low toxicity of ip mimo, lack of mutagenic effect.

Gee! The compounds of the invention are valuable nicotinic cholinergic receptor modulators. Some compounds that are antagonists at the nicotinic ASA receptor can be used to treat temporary anoxia and the resulting neurodegeneration.

Ge) The object of the invention is to create new 8-azabicyclo|3,2,1|oct-2-ene and -octane, which can be used for the treatment of a group of diseases, conditions or disorders, which are characterized by a decrease in cholinergic function or susceptibility to the action AC nicotinic receptor modulators. Another task of the invention is to create new pharmaceutical compositions with such compounds and methods of their preparation and therapeutic use.

Another object of the invention is to create new compounds that have some or all of the following favorable properties: high selectivity of binding to subtypes of the neuronal pASNK receptor, on (F, for example, subtype A?7, to low affinity to the muscle subtype, promotion cell survival, in the efficiency of attention stimulation during oral administration of ip mimo (rat model), low toxicity of ip mimo, absence of mutagenic effect.

Other tasks, which are clear to a specialist, are outlined below.

In the following text, "treatment" includes the treatment, prevention, or amelioration of a disease, and 65 "disease" means a disease, disorder, or condition.

The term "modulator" includes agonists, partial agonists, antagonists and allosteric modulators.

Central nervous system disorders include, for example, neurodegenerative disorders, memory or recognition dysfunction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Tourette's syndrome, attention deficit hyperactivity disorder, anxiety disorder, manic-depressive disorder, schizophrenia, obsessive compulsive disorder, eating disorders eg binge eating disorder, bulimia nervosa and obesity, narcolepsy, nociception, memory loss or dysfunction, AIDS-related dementia, senile dementia, peripheral neuropathy, learning disability, cognitive impairment , attention deficit, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, chronic fatigue syndrome, sleep disorders, pseudo-weakness, 7/0 Hanser syndrome, premenstrual syndrome, chronic fatigue syndrome, premature ejaculation, difficult erection , sleep disorders, mutism or trichocryptomania.

Inflammatory conditions include, for example, inflammatory skin disorders such as acne and rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and diarrhea.

Diseases associated with contractions of smooth muscles include, for example, convulsive disorders, adiposis, premature birth, convulsions, diarrhea, asthma, epilepsy, slow dyskinesia, hyperkinesia.

Pains include, for example, chronic, acute and recurrent pain, postoperative pain, migraine or phantom limb pain.

Substance abuse includes smoking, as well as the use of other nicotine-containing products, the use of opioids such as heroin, cocaine and morphine, the use of benzodiazepines or alcohol. In this regard, "treatment" includes treatment, prevention and relief of withdrawal and withdrawal symptoms and treatment aimed at reducing the use of addictive substances.

The invention includes compounds (single or in combination) of formula 1 o and any of its enantiomers or their mixtures, or its pharmaceutically acceptable salts, where ppp....1.- a single or double bond, K - hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl alkyl, aryl or arylalkyl, and rch- vi- « 9)

XX. at

Нв со б2- hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amine; or aryl, which may be singly or multiply substituted by substituents selected from the group consisting of 1-0 alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkyl, cycloalkyl, thioalkyl, thiocycloalkyl, methylenedioxy, aryloxy, halogen, SEZ, OSEZ, CM , an amino group, an aminoacyl group, a nitro group, an aryl and a monocyclic 5- or b-heteroaryl group; " di or monocyclic 5- or b--linked heteroaryl group, which can be single or multiple substituted -o by substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkyl, cycloalkyl, thiaalkyl, thiocycloalkyl, methylenedioxyl, aryloxyl, halogen, CEz, OSEz, CM, :z» amino group, nitro group, aryl and monocyclic 5- or b--linked heteroaryl group; or a bicyclic heteroaryl group composed of a monocyclic 5- or b-heteroaryl group fused to a benzene ring or with another monocyclic 5- or b-heteroaryl group, which may be single or multiple substituted by substituents , selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkyl, cycloalkyl, thioalkyl, thiocycloalkyl, methylenedioxy, (ee) aryloxy, halogen, SEZ, OSEZ, CM, amino group, nitro group, aryl and monocyclic 5- or b --linen heteroaryl c group;

A preferred embodiment of the invention is a compound of formula 1, in which 50 d' is 29, where 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, amine;

HF) or aryl, singly or multiply substituted by substituents selected from the group consisting of cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkyl, cycloalkyl, thioalkyl, thiocycloalkyl, methylenedioxy, o aryloxyl, OSEZ, CM, amino group, aminacyl group, nitro group, aryl and a monocyclic 5- or b-membered heteroaryl group; 60 or a monocyclic 5- or b--linked heteroaryl group, which can be single or multiple substituted by substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxyl, cycloalkyl, thisalkoxyl, thiocycloalkyl, methylenedioxyl, aryloxyl, halogen, CEz, OSEz, CM, nitro group, aryl and monocyclic 5- or b--heteroaryl group; or a bicyclic heteroaryl group composed of a monocyclic 5- or b-membered heteroaryl group with at least one heteroatom fused to a benzene ring or with another o monocyclic 5- or b-membered heteroaryl group, which can be single or multiple substituted by substituents, selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkyl, cycloalkyl, thioalkyl, thiocycloalkyl, methylenedioxy, aryloxy, halogen, CEz, OSEz3, CM, amino group, nitro group, aryl and monocyclic 5- or b--linked heteroaryl group.

Another preferred embodiment of the invention is a compound of formula 1, in which

K - hydrogen, methyl, ethyl or benzyl,

IN! - acetyl, 2-methoxyphenyl, 2-naphthyl, 3Z-acetamidophenyl, 2-selenophenyl Z-pyridyl, 3-(b-methoxy)pyridyl, 3-(6-chloro)pyridyl, 2-thiazolyl, Z-thienyl, 2- thienyl, 2-(3-methoxymethyl)thienyl, 2-furyl, 3-furyl, 70. 2-(3-bromo)thienyl, 3-chlorothien-2-yl, 3-(3-furyl)-2-thienyl, Z-quinolinyl, Z-benzofuryl, 2-benzofuryl,

3-benzothienyl, 2-benzothienyl, 2-benzothiazolyl, 2-thienyl, 3.2-yl, 2-(3-bromo)benzofuryl or 2-(3-bromo)benzothienyl.

Another embodiment of the invention is the above-mentioned compound, which is (5)-8-benzyl-3-(3-pyridyl)-8-azabicyclo|3.2.1|oct-2-ene) (5)-8-methyl-3- (Z-pyridyl)-8-azabicyclo|3.2.1|)oct-2-ene, (5)-8-methyl-3-(3-quinolinyl)-8-azabicyclo|3.2.PCoct-2-ene, ( 5)-3-(2-benzofuryl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene, (h5)-3-(2-benzothienyl)-8-methyl-8-azabicyclo|3.2 .1oct-2-ene, (h)-3-(23-thiazolyl)-8-methyl-8-azabicyclo|3.2.PDoct-2-ene, (5)-8-methyl-3-(2-methoxyphenyl) -8-azabicyclo|3.2.oct-2-ene, (5)-8-methyl-3-(3-thienyl)-8-azabicycloi|3.2. Oct-2-ene, (5)-8-methyl-3-(2-naphthyl)-8-azabicyclo|3.2.1|oct-2-ene, exo-8-methyl-3-(3-pyridyl)- 8-azabicyclo|3.2.1octane, (z)-8-H-3-(Z-pyridyl)-8-azabicyclo|3.2.oct-2-ene, (5)-8-methyl-3-I3-(b -methoxy)pyridyl|)|-8-azabicyclo|3.2.1)oct-2-ene, Ha (5)-3-acetyl-8-methyl-8-azabicyclo|3.2.1)oct-2-ene, ( 5)-8-methyl-3-I3-(b-chloro)pyridyl|/|-8-azabicyclo|3.2.1|oia-2-ene, i9) (5)-3-(2-benzofuryl)-8 -methyl-8-azabicyclo|3.2.1|oct-2-ene, (z)-3-(2-benzothienyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene, (5) -3-(3-acetamidophenyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene, rch- (5)-3-(3-aminophenyl)-8-methyl-8-azabicyclo|3.2 .1|oct-2-ene, (z)-3-(2-thienyl)-8-methyl-8-azabicycloi|3.2. Zoct-2-ene, M (5)-3-(2-(3-methoxymethylthienyl)|-8-methyl-8-azabicyclo|3.2.PDoct-2-ene, so (5)-3-(2-benzothiazole )-8-methyl-8-azabicycloI3.2.1 |oct-2-ene, (5)-3-(2-furyl)-8-methyl-8-azabicyclo|3.2, Oct-2-ene, so (z) -3-(2-thieno|3.2-5Hyenyl)-8-methyl-8-azabicyclo|3.2.1|)oct-2-ene, He) (z)-3-(2-thieno(2.3-Hyhienyl)- 8-methyl-8-azabicyclo|3.2.1|)oct-2-ene, (5)-3-(2-selenophenyl)-8-methyl-8-azabicyclo|3.2.oct-2-ene, (13- 3-(2-benzofuryl)-8-H-8-azabicyclo|3.2.Zoct-2-ene, "(z)-3-3-(3-furyl)-2-thienyl)|-8-H-8 -azabicycloi|3.2. Zoct-2-ene, (5)-3-(2-benzofuryl)-8-ethyl-8-azabicycloi|3.2. Oct-2-ene, - c (z)-3-(2-(3-bromothienyl)|-8-methyl-8-azabicyclo|3.2.PDoct-2-ene, and (g)-3-I(2 -(3-bromobenzofuryl))|-8-methyl-8-azabicyclo|3.2.Doct-2-ene, "» (5)-3-(2-(3-bromobenzothienyl)|-8-methyl-8-azabicyclo |3.2.1|)oct-2-ene, 3-(2-(3-chlorothienyl)|-8-methyl-8-azabicycloi|3.2. Oct-2-ene, (z)-3-3-(3 -furyl)-2-thienyl|-8-methyl-8-azabicyclo|3.2.oct-2-ene,

Ge") or their pharmaceutically acceptable acid additive salts; The invention also includes: a pharmaceutical composition with a therapeutically effective amount of a compound according to the invention or its pharmaceutically acceptable acid addition salt together with at least one pharmaceutically acceptable carrier or filler; use of a compound according to the invention for the manufacture of a medicament suitable for the treatment or prevention of such a condition, disorder or disease of a living body of an animal, including a human, which is sensitive to the action of nicotinic receptor modulators; use of a compound according to the invention in the case where the disease there is pain, disease of the central nervous system, disease caused by contraction of smooth muscle, neurodegeneration, inflammation,

Substance abuse or withdrawal symptoms caused by stopping the use of the chemical; o the use indicated above in the case where the disease of the central nervous system is Alzheimer's disease, Parkinson's disease, memory dysfunction or attention deficit hyperactivity disorder; the use specified above in the case where the disease is an abuse of a chemical substance or withdrawal symptoms caused by the cessation of use of a chemical substance, and such abuse is smoking or the use of other nicotine-containing products, and the withdrawal symptoms are caused by the cessation of the use of nicotine-containing products.

In addition, the invention includes a method of preparing compounds according to the invention, which involves operations a) introducing the compound of formula b5

Vo; where YuK is defined above, in the reaction with the compound of the formula K-ii, where BC! defined above, followed by dehydrogenation of the resulting compound; b) introduction of a compound of the formula (where EB is defined above, into a reaction with a compound of the formula K!-X, where B! is defined above, and X is a halogen, boric acid or trialkylstanyl; or c) reduction of a compound of the formula

Vos- M -in and where B is defined above. The invention also includes: a method of treating a disease of a living body of an animal, including a human, sensitive to the action of nicotinic receptor modulators of ASIA, which involves the introduction of a therapeutically effective amount of a compound according to the invention into such a living body of an animal, including a human, that needs such treatment. the method mentioned above, in the case where said disease is pain, central nervous system disease, neurodegeneration, inflammation, chemical abuse or withdrawal symptoms caused by stopping the use of a chemical substance or a disease caused by contraction of smooth muscle, the method mentioned above, in the case when the disease of the central nervous system is a disease of

Alzheimer's disease, Parkinson's disease, memory dysfunction or hyperactivity with associated attention deficit; Ge) the method mentioned above, in the case where the disease is the abuse of a chemical substance or the withdrawal symptoms caused by the cessation of the use of the chemical substance, and such abuse is smoking or the use of other nicotine-containing products, and the withdrawal symptoms are caused by the cessation of the use of nicotine-containing products. t

Examples of pharmaceutically acceptable acid addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzene sulfonate, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate, and acetate. Methods of making such salts are well known to experts.

Other acids (for example, oxalic acid), which are not pharmaceutically acceptable, can be used for the preparation of intermediate salts in the preparation of the compounds according to the invention and their pharmaceutically acceptable acid addition salts.

Halogens include fluorine, chlorine, bromine or iodine. "

The term "alkyl" means a straight or branched chain of 1 to 2 carbon atoms, including (but not limited to) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl; methyl, c ethyl, propyl and isopropyl are preferred. c» The term "cycloalkyl" means cyclic alkyl of 3-7 carbon atoms, including (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "alkenyl" means a group of 3-7 carbon atoms with at least one double bond, including (but not limited to) ethenyl, 1,2- or 2,3-propenyl, 1,2- or 2,3- or 3,4-butenyl. b The term "alkynyl" means a group with 2-6 carbon atoms with at least one triple bond, including

Ge | (but not limited to) ethynyl, 1,2- or 2,3-propynyl, 1,2- or 2,3- or 3,4-butynyl.

Cycloalkylalkyl includes the above-defined cycloalkyl and alkyl, for example, cyclopropyl methyl. o Alkoxyl is O-alkyl, cycloalkoxyl is O-cycloalkyl, thisalkoxyl is 5-alkyl, thiocycloalkyl is "" 20 c3-cycloalkyl. -ch The amino group is MH", MH-alkyl or M-(alkt)".

Acyl is (C-O0)-B9 (C-8)B, where BO is alkyl, aluoxyl, aryl or aryloxyl.

Aminoacyl is MH-acyl.

Examples of a monocyclic 5- or b-membered heteroaryl group with 1-4 heteroatoms can be 59 oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl,

HF) thiazol-4-yl, thiazol-5-yl, isothiazol-Z-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-Z-yl, 7 1,2 ,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,5 -oxadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl . 4-pyridazinyl, 2-pyrazinyl, 3-pyrazinyl, 1-pyrazolyl, 4-pyrazolyl, tetrazolyl.

A bicyclic heteroaryl group formed by a 5- or β-membered monocyclic heteroaryl group fused to a benzene ring is the above-defined 5- or β-membered monocyclic heteroaryl group fused to a benzene ring or the above-defined 5- or β-h -len heteroaryl group; examples are 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|Z,2- v|hyenyl, thieno(2.3-bHyenyl.

Aryl is an aromatic hydrocarbon group, such as phenyl and naphthyl.

Aryloxyl is -O-aryl.

The compounds of the invention can be used in both non-solvate and solvate form with pharmaceutically acceptable solvents, for example, water, ethanol and the like.

It is understood that the compounds of the invention have several chiral centers and exist in the form of isomers (eg, enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Racemic forms can be separated into optical antipodes by known methods, for example, by separating them into diastereomer salts with an optically active acid and separating the optically active amine compound with a base.

Another way of distinguishing racemates is based on chromatography on an optically active matrix. Racemic compounds according to the invention can thus be resolved into their optical antipodes, for example by fractional crystallization of salts such as 4- or 1-"tartrates, mandelates or camphosulfonates). Compounds according to the invention can also be distinguished by the formation of diastereomeric amides by the reaction of compounds according to the invention with an optically active activated carboxylic acid, for example, a derivative of ()- or (-Y-phenylalanine, (g) or (-) phenylglycine, or (- - or (-)camphanic acid, or by the formation of diastereomeric carbamates by the reaction of compounds according to the invention with optically active chloroformate, etc.

Other methods known to specialists can be used to distinguish optical isomers (see, for example, -).dadtsevz, A.SoPei, 5.UMPep, "Epapiotege, Kaseta(ez apa Kezoiiishiopv", doip UMPeu apa Bopv, Mem

Hock, 1981).

Optically active compounds are made from optically active starting materials.

The compounds of the invention may be prepared by any known method suitable for the preparation of such compounds (see Examples below). The starting materials for the procedures described herein are known to those skilled in the art and may be prepared by known procedures or purchased commercially. with

Compounds according to the invention can be converted into other compounds according to the invention using known methods. The final products of the described reactions can be isolated by conventional means, for example, i) extraction, crystallization, distillation, chromatography, etc.

Biology

Nicotinic ASA receptors in the brain are pentameric structures formed by elements different from those found in skeletal muscles. The existing eight a-elements (A2-AZ9) and three B-elements (82-B4) are described. The dominant subtype with a high affinity for AC nicotinic receptors contains three AA4 elements and two 82 elements. -

The affinity of the compounds according to the invention to nicotinic ASA receptors was investigated in three ip s mio tests for inhibition of the binding of ZN-epibatidine, ZN-rotoxin and ZN-cytisine.

Inhibition of ZN-cytisine binding

The dominant subtype with high affinity for nicotine contains three elements a4 and two elements B2. pASIK (about the latter type can be selectively marked by the nicotine modulator - ZN-cytisine.

Fabric preparation

At 0-4"C, the cerebral cortex of rats of the UMiziag line (150-200 g) was homogenized for 20 seconds in 15 ml of Tgiz, NOSI "(5BOml, pH 7.4) with 120 mM Mass, 5 mM KS, imM MosIi" and 2.5 mM SasSi" in homogenizer YuOKha-Titakh. The homogenate was centrifuged at 270009 for 1 min. The supernatant was discarded and the pellets were resuspended in fresh ts buffer and centrifuged again. The resulting pellets were resuspended in fresh buffer (ZBml per 1g of original tissue) and used in the binding test. Test

Aliquots (500 μl) of the homogenate were added to 25 μl of the test solution and 25 μl of ZN-cytisine (1NM, final concentration) | after mixing, it was incubated at 27C for 9 hours. Nonspecific binding was determined from

Me. using (-)-nicotine (100μM, final concentration). After incubation, bml was added to the samples

Go! of ice-cold buffer and the mixture was poured directly into a glass fiber filter MUpaytap OR/C under suction, after which it was immediately washed with ice-cold buffer (2x5 ml). The level of radioactivity on the filters was determined with a conventional liquid scintillation counter. Specific binding is total binding minus nonspecific binding

ChT" 70 binding. -h Inhibition of binding of "H-bungarotoxin M" in rat brain

A-bungarotoxin is a peptide isolated from the venom of the snake Eiaridae Vypdagis ptiipsisis (Merz ei ai.,

Viospet. Viorpuz. Ke. Sottyp., 44(3), 711, 1971), which has a high affinity for neuronal and neuromuscular nicotinic receptors and acts as a strong antagonist. ZN-A-bungarotoxin binds to a single site and with a unique distribution in the rat brain (Siagke et al., U). Meishgovsi., 5, 1307-1315, 1985) (F) ZN-A-bungarotoxin marks pASNE, formed by the isoform of the A?7 element of the brain and the At isoform of the neuromuscular

GI node (Spapdeaikh, Rydia Kevz. Gotspa. Meshygovsi. Roipa.

Essay, 4, 21-168, 1990). Homooligomer A7 in oocytes has a higher permeability to calcium than in neuromuscular receptors and in some cases higher than MMOA channels (Zednieia ei ai., 9. Meshygovsi., 13, 596-604, 1993).

Fabric preparation

At 0-4"C, the cerebral cortex of rats of the U/iziag line (150-200 g) was homogenized for 10 seconds in 15 ml of 20 mM buffer

Stainless steel with 118 mm Masi, 48 mm KSI, 12 mm M495O); and 2.5 mM CaCl (pH 7.5) in an OKha-Tiggah homogenizer.

The homogenate was centrifuged at 270,000 for 1 min. The supernatant was discarded and the pellets were washed twice with 65 centrifugation at 270,009 for 1 min. in 20 ml of fresh buffer. The obtained granules were resuspended in fresh buffer with 0.0195 bovine serum albumin (35 ml per 1 g of original tissue) and used in the binding test.

Test

Aliquots (500 μl) of the homogenate were added to 25 μl of the test solution and 25 μl of ZN-A-bungarotoxin (2NM, final concentration) and, after mixing, were incubated at 377"C for 2 hours. Nonspecific binding was determined using (-)-nicotine (1 mM , final concentration.) After incubation, bml of ice-cold Nerez buffer with 0.0595 REI was added to the samples and the mixture was poured directly into a glass fiber filter UUpaytap SR/C (pre-impregnated in 0.196 RE! for at least bh) under suction and then immediately washed with ice-cold buffer (2x5ml). The level of radioactivity on the filters was determined by a conventional liquid scintillation counter 70. Specific binding is total binding minus non-specific binding.

Inhibition of ZN-epibatidine binding

Epibatidine is an alkaloid first isolated from the skin of the frog Eriredobagez igisoiog. It has been found to have a very high affinity for neuronal nicotinic receptors, on which it acts as a strong agonist. ZN-epibatidine binds to two sites in the rat brain, both of which have pharmacological profiles consistent with neuronal nicotinic receptors and a similar zonal distribution in the brain (Nocaiipo eya!., Moi.

RIagtaso)., 48, 280-237, 1995).

The high-affinity binding site for H-epibatidine is the binding site for the A482 element of nicotinic receptors. The low-affinity site has not yet been identified - it may be a second nicotinic receptor or a second site in the same receptor. The inability of A-bungarotoxin to compete for the binding sites of "H-epibatidine" indicates that none of the binding sites represents the nicotinic receptor from the A7 elements.

Fabric preparation

At 0-47"C, the forebrain of UMiviag rats (150-200g) was homogenized for 10-20s in 20ml of Ttgiv, NOSI (5BOml, pH 7.4) in a Shga-Tygah homogenizer. The tissue suspension was centrifuged at 270009 for 10 minutes.

The supernatant was discarded and the pellets were washed three times by centrifugation at 270,000 for 1 min. in 20 ml He) of fresh buffer. The obtained granules were resuspended in fresh buffer (400 ml per g of original tissue) and used in the binding test.

Test

Aliquots (2.0 ml) of the homogenate were added to 0.100 ml of the test solution and 0.100 ml of ЗН-epibatin (0.3 NM, final concentration - 30) and, after mixing, incubated at room temperature for an hour. Non-specific I binding was determined using (-)-nicotine (3 µM, final concentration). After incubation, 5 ml of ice-cold Nerez buffer with 0.0595 REI was added to the samples and the mixture was poured directly into a MUpaytap OR/C glass fiber filter (pre-soaked in 0.195 RE! for at least 20 min.) under suction, (ee) after which it was immediately washed with ice buffer (2x5 ml). The level of radioactivity on the filters was determined by a conventional liquid scintillation counter. Specific binding is total binding minus nonspecific i-o binding.

The results are given as IR values, that is, the concentration that inhibits the binding of the radioactive ligand by 5095. In the table, the numbers of the compounds correspond to the examples. with t

ISvo(μM) PSvo(μm) ISvo(μM) z

F so sh to" 4 8 o t

Pharmaceutical compositions because the invention also relates to novel pharmaceutical compositions containing a therapeutically effective amount of a compound according to the invention.

The compound according to the invention in therapy can be administered in its pure form, but it is preferable to use the active ingredient, alternatively, in the form of a pharmaceutically acceptable salt in a pharmaceutical composition together with one or more adjuvants, excipients, carriers and/or diluents. 65 In a preferred embodiment, the invention provides pharmaceutical compositions that contain a compound according to the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. Carriers must be "acceptable", i.e. compatible with other ingredients of the composition and harmless to the recipient.

Pharmaceutical compositions according to the invention can be intended for oral, nasal, local (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or have a form suitable for administration by inhalation or insufflation.

The compound according to the invention together with a conventional adjuvant, carrier or diluent can be given the form of dosage units of a pharmaceutical composition. Such forms for oral administration may be solid, such as tablets or filled capsules, or liquid, such as solutions, suspensions, emulsions, elixirs, or liquid-filled capsules. Dosage forms can be prescribed for rectal administration by suppositories, or parenteral administration (including subcutaneous) by injections of sterile solutions. Such pharmaceutical compositions and their dosage unit forms may contain conventional ingredients in conventional proportions with the addition of active compounds and may contain any effective amount of active ingredient dosed within daily dosages.

The compound according to the invention can be administered in various forms orally and parenterally. It is clear to a person skilled in the art that dosage forms may contain as an active ingredient or a compound according to the invention, or a pharmaceutically acceptable salt thereof.

In a pharmaceutical composition with a compound according to the invention, a pharmaceutically acceptable carrier can be either solid or liquid. Solid forms include powders, tablets, capsules, pills, wafers, suppositories, and dispersible granules. The solid carrier can be one or more substances that can act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants or be capsule material.

In powder form, the carrier is a finely ground solid mixed with a finely ground active ingredient.

In tablets, the active ingredient is mixed in the proper proportion with a carrier that has the necessary binding and) ability with subsequent giving of shape and size.

Powders and tablets contain from 5-1095 to about 7095 of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc. The term "preparation" includes the placement of the active compound in a carrier capsule, with or without an additional carrier, as well as the preparation of wafers and cakes. Solid forms suitable for oral administration include tablets, powders, capsules, pills, wafers and cakes.

To prepare suppositories, melt a low-melting wax, for example, a mixture of fatty acid, sodium glycerides, or cocoa butter, and homogeneously disperse the active component in it by stirring. This mixture is poured into suitable molds and cooled until solidification.

Compositions for vaginal introduction are made in the form of pessaries, tampons, creams, jellies, pastes, foams or irrigations, which, in addition to the active component, contain suitable carriers known to specialists.

Liquid compositions include solutions, suspensions and emulsions, for example, aqueous or in water-propylene glycol solutions. For example, liquid compositions for parenteral injections can be water-polyethylene-plus) with glycol solutions.

Therefore, compounds according to the invention can be part of compositions for parenteral administration;" (for example, by injection, for example, bolus or continuous infusion) and can have a single dosage form in the form of ampoules, charged syringes, low-volume infusions or multi-unit packages with the addition of preservatives. Compositions can be made in the form of suspensions, solutions or emulsions in oil or

Ge» aqueous media and contain auxiliary agents, for example, suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be a powder obtained by aseptic separation or lyophilization from a bo solution, which is mixed with an appropriate carrier, such as sterile pyrogen-free water, before use. o. o. Aqueous solutions for oral administration can be prepared by dissolving the active component in water with optional addition of suitable coloring agents, flavor additives, stabilizing and thickening agents. o Aqueous suspensions for oral administration can be prepared by dispersing ton-comele active

And the component in water with a viscous additive, for example, natural or synthetic rubber, resins, methylcellulose, sodium carboxymethylcellulose or other known suspending agents.

The invention also includes solid compositions intended for conversion immediately before use into a liquid form for oral administration. Such liquid forms can be solutions, suspensions and emulsions and can contain, in addition to the active ingredient, dyes, flavorings, stabilizers, buffers, artificial and

F) natural sweeteners, dispersants, thickeners, solubilizers, etc. ka The composition with the compound according to the invention, intended for local introduction into the epidermis, is made in the form of ointments, creams or lotions, or applied to a transdermal sticker. Ointments and creams can be made on a water or oil basis with the addition of appropriate thickening or gelling agents. Lotions can be made on a water or oil basis with the addition of one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickeners or coloring agents.

Compositions for local administration by mouth include cakes made from the active ingredient and a flavoring agent, of course, sucrose and gum or tragacanth; pastilles from the active ingredient on an inert basis, for example, gelatin and glycerin or sucrose and gum; mouthwash with an active ingredient and a suitable carrier.

Solutions or suspensions are injected directly into the nasal cavity by conventional means, for example, a pipette or a sprayer. Compositions can be supplied in single or multi-dose packaging. In the latter case, the patient, using a pipette, enters the appropriate predetermined amount of solution or suspension. At

Sprayer uses achieve this by using a spray metering device.

The introduction of the composition into the respiratory channels is carried out by an aerosol supplied in a pressurized tank with a suitable propellant, for example, chlorofluorocarbon, in particular, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or another suitable gas. The composition of the aerosol may include surfactants, for example, lecithin. Dosing is carried out using a valve. 70 In another embodiment, the active ingredient is a dry powder in admixture, for example, with a suitable powder base, for example lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone. The powder carrier forms jelly in the nasal cavity. Such compositions can be produced in dosage forms, for example, in capsules or cassettes made, for example, of gelatin, or in blister packs from which the powder can be administered by inhaler.

In compositions intended for introduction into the respiratory channels and compositions for intranasal administration, the compound has the form of small particles with a size of 5 μm or less. Such particles can be obtained in known ways, for example, by micronization.

If desired, compositions can be adapted for slow release.

It is desirable to make compositions in dosage forms, that is, divided into unit doses, which contain the appropriate

Amount of active ingredient. They can be supplied in packages, each of which contains a certain number of doses, for example, in the form of tablets, capsules and powders in vials or ampoules, wafers or cakes.

The preferred forms of the compositions are tablets or capsules for oral administration and liquid for intravenous administration and continuous infusion.

Doses should depend on the age, weight and condition of the patient receiving treatment, as well as on the method of administration, the type of dosage and the desired result. The most suitable therapeutic unit doses are believed to be from about 0.1 to about 50mg, preferably from about 1 to about 100mg, most preferably from (8) about 1 to about 1mg of active ingredient.

In some cases, satisfactory results can be obtained using doses as low as 0.005 mg/kg for intravenous administration and 0.01 mg/kg for oral administration. The upper limit of the dose is 1Omg/kg with M zo Intravenous administration and 100mg/kg with oral administration. Preferred ranges are from about 0.001 to about 1 mg/kg when administered intravenously and from about 0.1 to about 1 mg/kg when administered orally. -

The method of treatment of co

The compounds according to the invention are strong modulators of the nicotinic receptor ASI and therefore can be used for the treatment of a large number of diseases, including cholinergic dysfunction, as well as disorders sensitive to the action of modulators of the nicotinic receptor ASI. These compounds may be used to treat, prevent, or alleviate diseases, disorders, or conditions of the central nervous system such as neurodegenerative disorders, memory or recognition dysfunction, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Tourette's syndrome, attention deficit hyperactivity disorder, anxiety disorder, manic-depressive disorder, schizophrenia, obsessive-compulsive disorder, "eating disorders, eg, binge eating disorder, bulimia nervosa, obesity, narcolepsy, nociception, memory loss or with c dysfunction , dementia caused by AIDS, senile dementia, peripheral neuropathy, deficiency. learning disabilities, cognitive impairment, attention deficit, autism, dyslexia, slow dyskinesia, and? hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, chronic fatigue syndrome, sleep disorders, pseudo-feminity, Hanser syndrome, premenstrual syndrome, chronic fatigue syndrome, premature ejaculation, erectile dysfunction, sleep disorders, mutism, or trichocryptomania. b Compounds of the invention can be used to treat inflammatory conditions including, for example, inflammatory skin disorders such as acne and rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea. Compounds according to the invention can also be used for the treatment of diseases associated with smooth muscle contractions, including, for example, convulsive disorders, adiposis, premature labor, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia.

And the compounds of the invention can also be used to treat pain, including, for example, chronic, acute and recurrent pain, post-operative pain, migraine or phantom limb pain.

The compounds according to the invention can help against substance abuse, including smoking, as well as the use of other nicotine-containing products, the use of opioids, for example, heroin, cocaine and morphine, the use of benzodiazepines or alcohol. In this regard, "treatment" includes treatment, prevention and

F) alleviation of withdrawal and withdrawal symptoms and treatment aimed at voluntary reduction of the use of addictive substances.

Daily doses are in the range of 0.1-500mg, preferably 10-7Omg (taken twice a day) depending on the method and form of administration, indication, patient weight as prescribed by the doctor or veterinarian.

The following examples illustrate the invention without limiting it. In the examples, all reactions with air-sensitive reagents are carried out in a nitrogen atmosphere and in anhydrous solutions. Drying is carried out over magnesium sulfate and the solvents are evaporated under vacuum.

Example A. 65 And. (73-8-benzyl-3-(3-pyridyl)-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

To a mixture of 11.0 g (69.7 mmol) of 3-bromopyridine and 200 ml of diethyl ether at -70"C, add butyllithium in hexane (2.5 M, 30.7 ml, 76 b/mmol) and stir for an hour. Add 15.0 g ( 69./mmol) of 8-benzyl-8-azabicyclo|3.2.1|octan-3-one, dissolved in 8 Oml of diethyl ether and stirred at 707C for 1 hour. During the night, the reaction mixture was cooled to room temperature, aqueous sodium hydroxide (1

M, 200 ml) and separate diethyl ether. The aqueous phase is extracted with ethyl acetate (3x100 ml), the organic phases are combined and after trituration with petroleum ether, 7.00 g (3496) of endo-8-benzyl-3-hydroxy-3-(3-pyridyl)-8-azabicyclo|3.2 are separated .1|octane. A mixture of 3,Og (10.2 mmol) endo-8-benzyl-3-hydroxy-3-(3-pyridyl)-8-azabicyclo|3.2.1|octane, 1 ml (12 mol) of thionyl chloride and 10000 ml of THF is stirred at 507"С for 0.5 hours. The mixture is evaporated and 4.6 mg (82.0 mmol) of potassium hydroxide 70, 25 ml of ethanol and 25 ml of water are added and stirred for 5 minutes. Ethanol is evaporated, 5 ml of water is added and extracted with ethyl acetate (2 x 50 ml). Chromatography on silica gel with DCM , methanol and concentrated ammonia (89:10:1) gives the desired compound in the form of a free base (2.2 g, 7895). The corresponding salt is obtained by adding a mixture of diethyl ether and methanol (9:1) saturated with fumaric acid. Melting point 142-14676. 2a. (5)-8-methyl-3-(33-pyridyl)-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

Prepared from 8-methyl-8-azabicyclo|3.2.1|octan-3-one according to the procedure of Example A. Temp, melting point. 124-12676.

By. (g)-8-methyl-3-(3-quinolinyl)-8-azabicyclo(|3.2.1|oct-2-ene salt of fumaric acid.

Prepared from 8-methyl-8-azabicyclo|3.2.1)octan-3-one according to the procedure of Example A. Temp, melting point. 140.8-143.820. yes (5)-3-(3-benzofuryl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

Prepared according to the procedure of Example A. Temp, melting point. 140.9-142.876.

Ba. (g)-3-(3Z-benzothienyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

Prepared according to the procedure of Example A. Temp, melting point. 146.6-149.576. ba. (g)-3-(23-thiazolyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

Prepared from 8-methyl-8-azabicyclo|3.2.1)octan-3-one according to the procedure of Example A. Temp, melting point. 196.3-198.570. and. (i)-8-methyl-3-(2-methoxyphenyl)-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid. high school

It is prepared from 8-methyl-8-azabicyclo|3.2.1|octan-3-one according to the procedure of Example A. va. (g)-8-methyl-3-(3-thienyl)-8-azabicyclo|3.2.1|oct-2-enoic salt of hydrochloric acid. and)

Prepared from 8-methyl-8-azabicyclo|3.2.1|octan-3-one according to the procedure of Example A. Temp, melting point. 117-118,576.

By. (g)-8-methyl-3-(2-naphthyl)-8-azabicycloi|3.2. Zoct-2-ene salt of hydrochloric acid.

Prepared from 8-methyl-8-azabicyclo|3.2.1|octan-3-one according to the procedure of Example A. Temp, melting point. 259-264276. M zo 1ba. Exo-8-methyl-3-(3-pyridyl)-8-azabicyclo|3.2.T|octane dihydrochloride. 1.5g (b.9mmol) mixture of endo- and exo-3-hydroxy-8-methyl-3-(33-pyridyl)-8-azabicyclo|3.2.T|octanes, 20.0g - (5090-na suspension in water) Raney nickel and Homl ethanol are mixed under reflux for 15 hours. The mixture is filtered and chromatographed on silica gel with DCM, methanol and conc. with ammonia (89:10:1) gives the desired compound as the free base. The corresponding salt is obtained by adding hydrochloride in methanol (0.55 g, 2990). co

Temp. 275-280. "about 11a.. Endo-3-hydroxy-3-(3Z-pyridyl)-8-tert-butoxycarbonyl-8-azabicycloi|3.2.1|-octane.

A mixture of 3,Og (10.2 mmol) endo-8-benzyl-3-hydroxy-3-(33-pyridyl)-8-azabicyclo-I3.2.1|octane, 0.80 g (5965) palladium on carbon, 2 ml conc. of hydrochloric acid and 75 ml of ethanol are stirred in a hydrogen atmosphere for 15 hours. The mixture is filtered through brownmillerite, evaporated to dryness and stirred for 33.5 hours. « 40.3 41 g (40.0 mmol) of triethylamine, 1.75 g (8.0 mmol) of di(tert-butoxycarbonyl) anhydride and 5 bOml of DCM, after which it is subjected to evaporation. Chromatography on silica gel with DCM, methanol and conc. with ammonia (89:10:1) gives 2.8 g (90965). of the desired compound. Temp. 90-9276. and?" 12a. (h-)-3-(3-pyridyl)-8-tert-butoxycarbonyl-8-azabicyclo/|3.2.1|-oct-2-ene.

A mixture of 2.0 g (b,bmmol) endo-3-hydroxy-3-(3Z-pyridyl)-8-tert-butoxycarbonyl-8-azabicyclo|3.2.1)octane, bml (82mmol) thionyl chloride, its T0b0ml THF is stirred at 5073 within 0.5 hours. The mixture is subjected to evaporation,

3.0 g (53 mmol) of potassium chloride, 20 ml of ethanol, and 20 ml of water are added to the mixture and stirred for 1 min, after which the ethanol is evaporated and 5 ml of water is added. The mixture is extracted with ethyl acetate (2x5Oml) and chromatographed on silica gel with DCM, methanol and conc. with ammonia (89:10:11) gives 0.43 g (2395) of the desired compound. 2) Example B. 16. (-3-8-H-3-(3Z-pyridyl)-8-azabicycloi|3.2. Zoct-2-ene salt of fumaric acid. ve Mixture O40g 0 (1.4Omol) (w5) -3-(3-pyridyl)-8-tert-butoxycarbonyl-8-azabicyclo|3.2.1|oct-2-ene, 3.2 g "M (28 mmol) trifluoroacetic acid and DCM are stirred overnight. Add aqueous sodium hydroxide ( 100ml, 1M) and the mixture was extracted with DCM (3x100ml). Chromatography on silica gel with DCM, methanol and conc. ammonia (89:10:1) gave the pure desired compound. The corresponding salt (0.13g, 3190) was obtained by adding a mixture of diethyl ether and of methanol two (97), saturated with fumaric acid. Temp, m.p. 175-1767c, 26. (5)-8-methyl-3-trifluoromethanesulfonyloxy-8-azabicyclo!/3.2.1 |oct-2-ene.

F) Sodium bis(trimethylsilyl)amide in THF ( 77.Bml, 77.5 mmol).The mixture is stirred at -707"C for 3 minutes. and add 32.5 g (90.9 mmol) of M-phenyl-bis(trifluoromethanesulfonamide) in THF (200 ml), after which it is slowly brought to room temperature and stirred overnight. Add aqueous sodium hydroxide (500 ml,

O.1M) and the mixture is extracted with ethyl acetate (2x200ml). Chromatography on silica gel with DCM and 1095 methanol gave 16.2 g (4595) of the desired compound as an oil. 36. (h)-8-methyl-3-I3-(b-methoxy)pyridyl)-8-azabicycloi|3.2.1 |oct-2-ene.

A mixture of 3,Og (12.2 mmol) (x)-8-methyl-3-trifluoromethanesulfonyloxy-8-azabicyclo|3.2.1|oct-2-ene, - 4.0 g 65 (12.2 mmol) hexamethylditin, 0.43 g (0.61 mmol) of bis(triphenylphosphine) palladium (II) chloride and 0.52 g (12.3 mmol) of lithium chloride are stirred in 1,4-dioxane (25 ml) for 2 hours. at 70"C. Add 4.6 bg (24.4 mmol)

C-bromo-6-methoxypyridine and stirred under reflux overnight. The solvent is evaporated, aqueous sodium hydroxide (30ml, 1M) is added and the mixture is extracted with ethyl acetate (3x30ml). Chromatography on silica gel with DCM, methanol and conc. with ammonia (89:10:1) gives 1.0 g (3695) of the desired compound. 46. (5)-3-acetyl-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

A mixture of 2.0 g (7.А4 mmol) (w)-8-methyl-3-trifluoromethanesulfonyloxy-8-azabicyclo|3.2.1|oct-2-ene, -2.45 g (11.immol) 1-methoxy-1- of trimethylstannylethylene, 0.26 g (0.37 mmol) of bis(triphenylphosphine) palladium (II) dichloride and 0.31 g (7.4 mmol) of lithium chloride are stirred in THF (3 mL) under reflux overnight.

The solvent is evaporated, aqueous sodium hydroxide (40ml, 1M) is added and the mixture is extracted with ethyl acetate. Temp, 7/0 melt. 148.5-1507C. Chromatography on silica gel with DCM, methanol and conc. with ammonia (89:10:11) gives 0.23 g (1790) of (z)-3-(1-methoxy-1-ethenyl)-8-methyl-8-azabicyclo|3.2.1)oct-2-ene fumaric salt acid, which is mixed with hydrogen chloride in methanol (1 Oml, 4.5 M) for 1 min. The mixture is evaporated to dryness and added

0.19 g (8.4 mmol) of sodium ethoxide. Chromatography on silica gel with DCM, methanol and conc. with ammonia (89:10:1) gives the desired compound. The corresponding salt (0.21 g, 58906) is obtained by adding a mixture of diethyl ether and methanol (9:1), /5 saturated with fumaric acid. Temp. 175-1767S. 56. (-)-8-methyl-3-I3-(b-chloro)pyridyl)-8-azabicycloi|3.2. Zoct-2-ene salt of fumaric acid.

A mixture of 0.5 g (2.13 mmol) (5)-8-methyl-3-I3-(b-methoxy)pyridyl|)|-8-azabicyclo!|3.2.PDoct-2-ene and 4 ml of phosphorus oxychloride in 1 ml of DMF stir overnight at 957C. Add ice (100g) and aqueous sodium hydroxide (5Oml, 4M) and the mixture is extracted with ethyl acetate (3x50ml). Chromatography on silica gel with DCM, methanol and

Conc. with ammonia (89:10:11) gives the desired compound as an oil. The corresponding salt (0.35 g, 4795) is obtained by adding a mixture of diethyl ether and methanol (9:1) saturated with fumaric acid. Temp. 140-14276. 66. (7)-8-methyl-3-trifluoromethanesulfonyloxy-8-azabicycloi|3.2.1 |oct-2-ene.

Sodium bis(trimethylsilyl)amide in THF (73.9 ml, 73.9 mmol).The mixture is stirred at -707"C for 10 minutes. and 24.0 g (67.2 mmol) of M-phenyl-bis(trifluoromethanesulfonamide) are added to the mixture, then slowly cooled to room temperature and stirred overnight. Aqueous sodium hydroxide (350ml, 0.1M) is added and the mixture is extracted with ethyl acetate (2x150ml). Chromatography on silica gel with DCM and 1096 methanol gave 11.6 g (70905) of the desired compound as a brown oil.

Example B M zo 1c. (-3-3--2-benzofuryl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

A mixture of 1.5 g (b,1mmol) /(g)-8-methyl-3-trifluoromethanesulfonyloxy-8-azabicyclo|3.2.1|oct-2-ene, -0.99g - (b,1mmol) benzofuran-2 -boric acid, 0.07g (0.0bmmol) tetrakis(triphenylphosphine)ipalladium (0), 0.26g (6b.1mmol) lithium chloride, 4.2g (30.5mmol) potassium carbonate, 15ml water and 15ml 1, 2-dimethoxyethane is kept under reflux for 1.5 hours. Add 50 ml of water and extract the mixture with ethyl acetate (2 x 330 ml). co

Chromatography on silica gel with DCM, methanol and conc. with ammonia (89:10:1) gives the desired compound. The corresponding salt (0.24 g, 1190) is obtained by adding a mixture of diethyl ether and methanol (9:1) saturated with fumaric acid.

Temp. 188.3-190.976. 28. (5)-3-(2-benzothienyl)-8-methyl-8-azabicycloi|3.2. Tsokt-2-en.

Prepared according to Example B. Temp, melt. 81.0 - 83.670. "

Zv. (g)-3-(3-acetamidophenyl)-8-methyl-8-azabicycloi|3.2. Zoct-2-ene salt of fumaric acid. with c Prepare according to Example B from 3-acetamidobenzeneboronic acid. Temp. 195.3 - 196.976. . 4 in. (5)-3-(3-aminophenyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid. and?" A mixture of 0.32 g (1.2 b5 mmol) of (x)-3-3-acetamidophenyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene and 2 Bml (25965) of hydrochloric acid is stirred under reflux for at night The mixture is evaporated to dryness, aqueous sodium hydroxide (5Oml, 1M) is added and the mixture is extracted with ethyl acetate (2x50ml), obtaining

F 0.22g (52905) of the desired compound. Temp. 195.3-196.976.

Example G. so 1g. (5)-3-(2-benzofuryl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid. 2) Butyllithium in hexane (2.5 M, 75 ml, 18 mmol) is added to a mixture of 20.0 g (169.3 mmol) of benzofuran and 200 ml of diethyl ether at 0 °C. The mixture is stirred at 0 °C for 0.5 h. and after cooling to -70°C, 23.0 g (169.3 mmol) of 8-benzyl-8-azabicyclo|3.2.octan-3-one dissolved in 150 ml of diethyl ether are added. The reaction "M" mixture is stirred for an hour. and slowly brought to room temperature overnight. Add 200 ml of water and filter out 38.7 g (89905) of endo- and exo-3-(2-benzofuryl)-3-hydroxy-8-methyl-8-azabicyclo|3.2.1|octane. A mixture of endo- and exo-3-(2-benzofuryl)-3-hydroxy-8-methyl-8-azabicycloi|3.2.1|octanes (30,Og, 116,bml), ZbBml conc. of hydrochloric acid and 300 ml of ethanol are mixed under reflux for an hour. Solvent

F) evaporate, add aqueous sodium hydroxide (15Oml, 4M), extract the mixture with ethyl acetate (2x1O0Oml) and separate 18.9g (70905). (5)-3-(2-benzofuranyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene. The corresponding salt is obtained by adding a mixture of diethyl ether and methanol (9:11), saturated with fumaric acid. Temp. because 188.5-191.276. 2 years Hydrochloride (5)-3-(2-benzothienyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene.

It is prepared according to Method G. Temp, melt. 225076.

According to (5)-3-(2-thienyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

It is prepared according to Method G. Temp, melt. 141.5 - 143.576. 65 4g. (5)-3-(2-(3-methoxymethylthienyl)|-8-methyl-8-azabicyclo|3.2.oct-2-ene.

It is prepared according to Method G and obtained in the form of oil.

God (5)-3-(2-benzothiazolyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

It is prepared according to Method G. Temp, melt. 195-196,870. Mr. (-)-3-(2-benzothiazolyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

Prepare according to Method G except for the metallation temperature, under reflux and with 1.2 equiv. tetramethylethylenediamine. 7 years (5)-3-(2-furyl)-8-methyl-8-azabicycloi|3.2.1 |oct-2-ene.

It is prepared according to Method G and obtained in the form of oil. g. (z)-3-(2-thienoyl3.2-B)hyenyl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of oxalic acid. 70 Prepared according to Method G. Temp, melt. 48-50.

Oh (z)-3-(2-thieno(2.3-bighenyl)-8-methyl-8-azabicycloi|3.2. Zoct-2-ene salt of oxalic acid.

It is prepared according to the Method of Temp. 46-4870. 10 g.. (-3-3--2-selenophenyl)-8-methyl-8-azabicyclo/|3.2.1|)oct-2-ene.

It is prepared according to Method G. Temp, melt. 176.8-178.370.

Method D

Td. (5)-3-(2-benzofuryl)-8-H-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

A mixture of 54 g (22.bmmol) /(g)-3-(2-benzofuryl)-8-methyl-8-azabicyclo|3.2.1|oct-2-ene, 5.0 g (34.7 mmol) of 1-chloroethyl chloroformate and 25 ml of xylene is kept under reflux for 2 hours. Methanol is added and the mixture is stirred under reflux for 2 hours. At room temperature, aqueous sodium hydroxide (50ml, 4M) was added and the mixture was extracted with ethyl acetate. Chromatography on silica gel with DCM, methanol and conc. with ammonia (89:10:11) gives the desired compound. The corresponding salt (2.58 g, 3390) is obtained by adding a mixture of diethyl ether and methanol (9:11) saturated with fumaric acid. Temp. 201-204" 2d. (g)-3-I3-(3-furyl)-2-thienyl|-8-H-8-azabicycloi|3.2. Zoct-2-ene salt of fumaric acid.

Prepare according to Example D from (5)-3-3-(3-furyl)-2-thienyl|-3-methyl-8-azabicyclo|3.2.PDoct-2-ene. Temp, sea level. 187-1897S

Ex. (5)-3-(2-benzofuryl)-8-ethyl-8-azabicyclo|3.2. Zoct-2-ene salt of fumaric acid. and)

A mixture of 1.5 g (6 b, 7 mmol) (x5)-3-(2-benzofuryl)-8-H-8-azabicyclo|3.2.1|oct-2-ene, 0.8 g (7.3 mmol) of bromoethane, 0 .87 g (6b.7mmol) of diisopropylethylamine and bbml of DMF are stirred for 2 hours, aqueous sodium hydroxide (100ml, 1M) is added and the mixture is extracted with diethyl ether (2x100ml). Chromatography on silica gel with DCM, methanol Kk zo | conc. with ammonia (89:10:11) gives the desired compound. The corresponding salt (0.77 g, 3195) is obtained by adding a mixture of diethyl ether and methanol (9:1) saturated with fumaric acid. Temp. 197-2037С -

Example E p

That. (5)-3-I2-(3-bromothienyl)|-8-methyl-8-azabicyclo|3.2.oct-2-ene,

Lithium diisopropylamide (2M, so 168.7 mmol) is added to a solution of 25.0 g (153.3 mmol) of Z-bromothiophene in 250 ml of THF at -807C, and at -80"C the mixture is stirred for 1 hour, 21.3 g (153.3 mmol) are added ) of tropinone in 200 ml of THF and stirred for 1 h, after which the temperature of the mixture was brought to room temperature overnight. Aqueous sodium hydroxide (200 ml, 1 M) was added and the mixture was extracted with diethyl ether (3 x 30 ml). Chromatography on silica gel with DCM, methanol and conc. ammonia (89:10:1) gives endo- and exo-3-3-3-bromo-(2-thienyl)|-3-hydroxy-8-methyl-8-azabicyclo|3.2.1|octanes. A mixture of endo- and "exo-3-3-bromo-(2-thienyl)|-3-hydroxy-8-methyl-8-azabicyclo!|3.2.1)-octanes (8.85g, 29.3ml) and CONC. pla) with hydrochloric acid is stirred for an hour. Hydrochloric acid is evaporated, aqueous sodium hydroxide (200 ml, 1 M) is added, the mixture is extracted with ethyl acetate (2 x 100 ml), obtaining 8.3 g (10095) of the desired compound a. The corresponding salt (0.24 g, 11965) is obtained by adding a mixture of diethyl ether and methanol (9:1), sat enoic fumaric acid. Temp. 130-13270. 2e. (z)-3-(2-(3-bromobenzofuryl))|-8-methyl-8-azabicyclo|3.2.1|oct-2-ene salt of fumaric acid.

Ge» Prepared according to Example E. Temp, melt. 161.4-163.370.

Ze. (5)-3-(2-(3-bromobenzothienyl)|-8-methyl-8-azabicyclo/|3.2.1|oct-2-ene salt of fumaric acid. It is prepared according to Example E. Temp, m.p. 165 ,0-166,970. 2) 4e. 3-(2-(3-chlorothienyl)|-8-methyl-8-azabicycloi|3.2, Zoct-2-ene salt of fumaric acid.

Prepared according to Example E. Temp, melt. 151.5-153.570. in Be. (g)-3-3-(3-furyl)-2-thienyl|-1-methyl-8-azabicycloi|3.2.1|oct-2-ene salt of fumaric acid. "M Mixture 2.0g (7.00mmol) (x)-3-3-(3-bromothienyl)|-8-ethyl-8-azabiy,yl|3.2.1|oct-2-ene, 0.94g ( 84 mmol)

Z-furylboric acid, 0.16g (0.14mmol) tetrakis(triphenylphosphine)palladium (0), 10.5ml (2M) aqueous potassium carbonate, 2.66g (35mmol) 1,3-propanediol, 1.2ml -dimethoxyethane and 5 Oml of dioxane are mixed under reflux in the refrigerator overnight. Add 50 ml of sodium hydroxide and extract the mixture with ethyl acetate (50 ml).

Chromatography on silica gel with DCM, methanol and conc. with ammonia (89:10:1) gives the desired compound. The corresponding salt (F, (1.59 g, 5995) is obtained by adding a mixture of diethyl ether and methanol (9:1), saturated with fumaric acid. ka Temp, melting point 187-18920.

Claims (10)

60 Formula of the invention 1. Derivative of 8-azabicycloi|3.2. Doct-2-ene of formula b5 where K is hydrogen, C is alkyl or C 5.6 alkenyl, or benzyl, and B! - a pyridyl, thiazolyl, thienyl or furyl group, in which the monocyclic heteroaryl can be optionally mono- or multi-substituted by substituents selected from the group consisting of alkyl, alkoxy, halogen, CE3, OSE3, CM and a nitro group, or quinolinyl, benzofuryl, benzothienyl, benzothiazolyl, thieno|3.2-BIhienyl, thieno|2.3-BIthienyl group, in which the bicyclic heteroaryl may be optionally mono- or polysubstituted by substituents selected from the group consisting of alkyl, alkyl, halogen, CEz, OSEz , CM, amino group and nitro group. 2. Derivative of 8-azabicycloi|3.2. Tsoct-2-ene according to claim 1, which differs in that K is hydrogen, methyl, ethyl or benzyl, in! - 3-pyridyl, 3-(6-methoxy)pyridyl, 3-(6-chloro)pyridyl, 2-thiazolyl, 3-thienyl, 2-thienyl, 2-(3-methoxymethyl)uthienyl, 2-furyl, 3- furyl, 2-(3-bromo)thienyl, Z-chlorothien-2-yl, Z-quinolinyl, Z-benzofuryl, 2-benzofuryl, Z-benzothienyl, 2-benzothienyl, 2-benzothiazolyl, 2-thienoY3.2-BIhienyl , thieno(2.3-BIhienyl, 2-(3-bromo)benzofuryl or 2-(3-bromo)benzothienyl. 3. Derivative of 8-azabicyclo|3.2.1)oct-2ene according to claim 2, which differs in that it is (7)-8-benzyl-3-(33-pyridyl)-8-azabicyclo|3.2.1| Oct-2-ene, (α)-β-methyl-3-(3-pyridyl)-8-azabicyclo|3.2.Poct-2-ene, (7)-8-methyl-3-(3-quinolinyl)- 8-azabicycloi|3.2. Zoct-2-ene, c (t)-3-(3-benzofuryl)-8-methyl-8-azabicyclo!|3.2. Zoct-2-ene, Ho) (5)-3-(3-benzothienyl)-8-methyl-8-azabicycloi|3.2. Oct-2-ene, (t)-3-(2-thiazolyl)-8-methyl-8-azabicyclo|3.2.PCoct-2-ene, (7 )-8-methyl-3-(3-thienyl)- 8-azabicyclo|3.2.1|oct-2-ene, rch- (5)-8-H-3-(3-pyridyl)-8-azabicycloi|3.2. Zoct-2-ene, (7 )-8-methyl-3-I(3-(b-methoxy)pyridyl)|-8-azabicyclo|3.2. Zoct-2-ene, (7 )-8-methyl- 3-(3-(b-chloro)pyridyl|-8-azabicyclo/|3.2.Doct-2-ene, me) (5 )-3-(2-benzofuryl)-8-methyl-8-azabicyclo!|3.2 . Zoct-2-ene, c (XE)-3-(2-benzothienyl)-8-methyl-8-azabicycloi|3.2. Oct-2-ene, c (5)-3-(2-thienyl)-8-methyl-8-azabicyclo|3.2.1|)oct-2-ene, (5)-3-(2-benzothiazolyl)- 8-methyl-8-azabicycloi|3.2. Zoct-2-ene, (7)3-3-(2-furyl)-8-methyl-8-azabicycloi|3.2. Oct-2-ene, (5 )-3-(2-thieno|3.2-β-hyenyl)-3-methyl-8-azabicycloi|3.2.Poct-2-ene, (5 )-3-(2-thieno| 2.3-5)hyenyl)-8-methyl-8-azabicyclo|3.2.Zoct-2-ene, ts (5)-3-(2-benzofuryl)-8-H-8-azabicycloi|3.2.1Pokt-2 -en, i » (7)3-3-(2-benzofuryl)-8-ethyl-8-azabicycloi|3.2. Zoct-2-ene, (i )-3-I(2-(3-bromothienyl)|-8-methyl-8-azabicycloi|3.2. Zoct-2-ene, 415 (5 )-3-(2-( 3-bromobenzofuryl)|-8-methyl-8-azabicycloi|3.2.1Poct-2-ene, b (7)3-3-(2-(3-bromobenzothienyl)|-8-methyl-8-azabicyclo|3.2. Oct-2-ene, 3-(2-(3-chlorothienyl)|-8-methyl-8-azabicycloi|3.2. Oct-2-ene, so or its pharmaceutically acceptable acid addition salts. oz 4. 8-azabicyclo|3.2.1|oct-2-ene derivative according to any one of claims 1 - C, which is characterized in that it is used for the manufacture of a medicament suitable for the treatment of such a disease in a mammal, including a human, which is sensitive to the action of AC nicotinic receptor modulators. "AND 5. 8-azabicyclo|3.2.1|oct-2-ene derivative according to claim 4, characterized in that the disease treated is pain, central nervous system disease, smooth muscle contractile disease, neurodegeneration, inflammation , substance abuse, or withdrawal symptoms caused by stopping the use of the chemical. 6. 8-azabicyclo|3.2.1|oct-2-ene derivative according to claim 5, characterized in that the disease being treated is F, Alzheimer's disease, Parkinson's disease, memory dysfunction or hyperactivity associated with attention deficit. co 7. An 8-azabicyclo|3.2.1|oct-2-ene derivative according to claim 5, characterized in that the disease being treated is chemical abuse or withdrawal symptoms caused by stopping the use of the chemical substance, and such abuse is smoking or use of other nicotine-containing products, and withdrawal symptoms are caused by stopping the use of nicotine-containing products. 8. Derivative of 8-azabicyclo|3.2.1|oct-2-ene according to claim 5, which differs in that the disease of the central nervous system is depression. 9. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 - 65 C or a pharmaceutically acceptable acid addition salt thereof together with at least one pharmaceutically acceptable carrier or excipient. 10. The method of obtaining a derivative of 8-azabicyclo|3.2.1)oct-2-ene according to claim 1, in which the compound of the formula | МА 0 О50,СЕ" where K is defined in claim 1, are introduced into the reaction with the compound of the formula VK 1-X, where B! defined in claim 1, and X is halogen, boric acid or /o trialkylethane. Ol. The method of obtaining the 8-azabicycloi derivative|3.2. Zoct-2-ene according to claim 1, in which the compound of the formula eight is reduced. | And where is V! is determined by clause 1. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 8, 15.08.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s (8) cha « so s (Se) shi s z (22) (ee) (95) iz 50 what F) has) 60 b5