UA75478C2 - Unsaturated 1-amino-alkylcyclohexane nmda, 5ht3 and antagonists of nicotinic receptor - Google Patents

Abstract

Unsaturated 1-amino-alkylcyclohexane compounds which are systemically-active as NMDA, 5HT3 and nicotinic receptor antagonists, pharmaceutical compositions comprising the same, method of preparation thereof, and method of treating CNS disorders which involve disturbances ofglutamatergic, serotoninergic, and nicotinic transmission, treating immunomodulatory disorders, and antimalaria, antitrypanosomal, anti-Borna virus, anti-HSV and anti-Hepatitis C virus activity.

Description

Description of the invention

Unsaturated 1-aminoalkylcyclohexane compounds, which are systemically active as antagonists of MMOA, 5-NO and 2 nicotinic receptors, including their pharmaceutical compositions, the method of their preparation and the method of treatment with their help of disorders of the central nervous system, which include disorders of glutamatergic, serotonergic and nicotinic transmission, for the treatment of immunomodulatory disorders and for the treatment of infectious diseases.

Antagonists of MMOA

Antagonism of M-methyl-O-aspartate (MMOA)-type glutamate receptors has potentially a wide range of 70 therapeutic applications (19). Functional inhibition of MMOA receptors can be achieved by affecting various restriction sites, such as the primary mediator site, the strychnine-sensitive glycine site (glycine b), the polyamine site, and the phencyclidine site located inside the cation channel. Channel blockers

MMOA receptors act in a non-competitive manner, which is "application dependent"; this means that they usually only block the channel in the open state. As many interpret, this dependence on the use of 72 means that stronger activation of the receptor should lead to a greater degree of antagonism. In addition, this mode of action is believed to imply that this class of antagonist may be particularly useful when overactivation of MMOA receptors is expected, such as in epilepsy, ischemia, and trauma. However, previous clinical practice with the use of a selective, high-affinity type strongly depends on the use of the non-competitive agonist of MMA receptors (g)-5-methyl-10,11-dihydro-5H-dibenzocycloheptene-5,10-imine maleate ((4 )-MK-801) is disappointing. Namely, therapeutic efficacy in epilepsy is low, while some psychotropic side effects are found at therapeutic doses. These observations, together with the fact that phencyclidine abusers experience similar psychotropic symptoms, suggest that noncompetitive MMOA receptor antagonism may not be a promising therapeutic approach.

However, the use of more complex electrophysiological methods shows that there is no equality between different non-competitive antagonists, since factors such as the speed of receptor blockade (on-off kinetics) and the stress dependence of this effect can determine the pharmacodynamic distinctive features of ip mimo, among others. , for example, with therapeutic safety. Paradoxically, agents with low to moderate affinity may be more likely to be suitable than agents with high affinity. Such discoveries initiated a review of the concept of non-competitive antagonism of MMOA receptors in the development of medicinal products (19, 22). Noncompetitive MMOA receptor antagonists such as amantadine and memantine, which satisfy the above criteria, have been used clinically for several years in the treatment of Parkinson's disease and dementia, respectively, and in fact rarely produce side effects at the therapeutic doses used in their respective indications. . oh

From the point of view of the above-mentioned rationale, the applicants have developed a series of new non-competitive antagonists of 30MMOA receptors based on the unsaturated 1-aminoalkylcyclohexane structure. This study was developed to compare the antagonistic properties of MMOA receptors of these unsaturated 1-aminoalkylcyclohexane derivatives in receptor binding studies, electrophysiological experiments, on one convulsive model and two models of motor impairment. Substitutions for these "unsaturated 1-aminoalkylcyclohexanes" are detailed in Table 6. Of 50 Antagonists of 5-HT3 receptors 5-HT3 receptors are ligand-gated ionotropic receptors permeable to cations. Receptors

Human 5-HT3 have the highest density on enterochromaffin cells in the gastrointestinal mucosa, which are stimulated by vagal afferents, and the brain stem agea, which forms a chemoreceptor trigger zone.

Since 5-HT3 receptors have a high density not only in the agea of the brain, but also in the area of the hippocampus. and the amygdala of the limbic system, suggest that 5-HT3-selective antagonists may provide 4! psychotropic effects | Ogeepezpamu 8: 5iimegwiope, 19971.

Indeed, early animal studies suggest that 5-HT receptor antagonists, in addition to their widely recognized antiemetic use, may be clinically useful in a number of areas. These areas include anxiety disorders, schizophrenia, drug and alcohol abuse, depressive disorders, cognitive impairment, Alzheimer's disease, cerebellar tremor, psychosis associated with the treatment of Parkinson's disease, co-pain (migraine and mucositis), and appetite disorders. .

Antagonists of neuronal nicotinic receptors

At this time, ten alpha subunits (alpha 1-10) and four beta subunits (beta 1-4) are known for nicotinic 29 receptors. A482 receptors are probably most common in the CNS, especially in the hippocampus and striatum.

HF) They form non-selective cation channels with slow, incompletely desensitizing currents (type I).

Homomeric A7 receptors are pre- and postsynaptic and are found in the hippocampus, the motor area of the brain and the limbic system, as well as in the peripheral autonomic nervous system. These receptors are characterized by their high Ca?2" permeability and rapid strongly desensitizing reactions (type IA). Changes in nicotinic receptors are involved in a number of diseases. These diseases include Alzheimer's disease,

Parkinson's, Tourette's syndrome, schizophrenia, drug abuse, nicotine abuse and pain.

Based on the observation that the nicotinic agonist nicotine appears to have beneficial effects by itself, drug development has thus far involved the discovery of selective nicotinic agonists.

On the other hand, it is unclear whether the effects of nicotinic agonists, for example, in Tourette's syndrome and schizophrenia, are due to activation or deactivation/desensitization of neuronal nicotinic receptors.

The effects of agonists on neuronal nicotinic receptors strongly depend on the period of exposure. Rapid reversible desensitization occurs in milliseconds, reduction occurs in seconds, irreversible deactivation of A482- and A7-containing receptors occurs in hours, and their upregulation occurs in days.

In other words: the effects of nicotinic "agonists" may actually be due to partial agonism, deactivation and/or desensitization of neuronal nicotinic receptors. In turn, moderate concentrations of neuronal nicotinic receptor channel blockers can produce effects similar to those reported for nicotinic agonists in the indications mentioned above.

At this time, it was found that a number of unsaturated 1-aminoalkylcyclohexanes have a sharply pronounced and unexpected antagonistic activity against MMOA, 5-HT3 and nicotinic receptors. Due to the above properties, these substances are suitable for the treatment of a wide range of disorders of the central nervous system, which include disorders of glutamatergic, serotonergic and nicotinic transmission, have an immunomodulatory effect (and properties against infectious diseases. These compounds are mainly found in the form of pharmaceutical compositions in which they are present together with one or more pharmaceutically acceptable diluents, carriers or fillers.

The purpose of this invention is new pharmaceutical compounds, which are unsaturated 1-aminoalkylcyclohexane antagonists of MMOA, 5-HT" and nicotinic receptors, and their pharmaceutical compositions.

In addition, the subject of this invention is a new method of treating, terminating, alleviating, weakening or reducing the intensity of unwanted disorders of the central nervous system, which include disorders of glutamatergic, serotonergic, nicotinic transmission, treatment of immunomodulatory disorders and treatment of infectious diseases using the compound of this invention or a pharmaceutical composition, which contains it. An additional subject of this invention is a method of obtaining unsaturated 1-aminoalkylcyclohexane active elements. Additional objects of the invention will become apparent hereinafter, and still others will be apparent to those skilled in the art.

Thus, according to the authors, the content of this invention can be summarized, among other things, in the following words: a compound selected from the compounds of formula I: i) 7 Ka eE s yich- - - | and -

Erva o 7 ee Kz 4 i - 7 ha Ve Z ;" where - B" means -"(A)n-(СВ 82) 4-МВ ЗВ; -I - pt, 1 or 2; - А is selected from the group containing linear or branched lower alkyl (C.i-Cv) , linear or branched i-th lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv);

Her - V' and V? independently selected from the group containing hydrogen, linear or branched lower alkyl(C.4-Cv), -1 50 linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv); - B3 and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (C.4-Cv), or together form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl substituted 3-7- -linen azacycloalkane or azacycloalkene; 59 - VE? independently selected from the group consisting of linear or branched lower alkyl (Ci-Cv), linear or

HF) branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv), or B? combines with the cu carbon to which it is attached and the neighboring carbon, forming a double bond; - Cr, Ku, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C--Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower bo alkynyl(Co- Sv), or Kr, Ka, K, and KC can independently combine with the carbon to which they are attached and the neighboring carbon, forming a double bond, or Kr, Ku, K, and K5 can independently form a double bond connection with ) or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from cyclohexane, because cyclohex-2-ene,

cyclohex-3-ene, cyclohexa-1,4-diene, cyclohexa-1,5-diene, cyclohexa-2,4-diene and cyclohexa-2,5-diene, and provided that at least one of K, and Ku is not hydrogen and at least one of K, and K» is not hydrogen, and provided that 0-7 is cyclohexane, if at least one of (A) 1(СВ'В) t, U , B, B, Vr,

Ka, Ki K5 represents a linear or branched lower alkenyl (C»o-Cv) or a linear or branched lower 70 alkynyl (Co-Cv); and its optical isomers and pharmaceutically acceptable additive salts of acids or bases; a method of treating existing animals to alleviate a condition treated by an MMOA antagonist, which comprises the step of administering to the animal an amount of a compound selected from the compounds of formula I: (8) where: A)n-(SV 82) 4-MA ZV; - pt, 1 or 2; « - A selected from the group containing linear or branched lower alkyl (Ci-Cv), linear or branched MU lower alkenyl (Co-Cv ) and linear or branched lower alkynyl (Co-Cv);

Z - B' and B? independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), - linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); - B3 and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv), or together « and form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or with (Co-Cv)alkenyl substituted 3- 7-lene azacycloalkane or azacycloalkene; c - B, Kr, Ka, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C.-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl (Co-Cv), or в, Кр, Ку, Кр, and К5 can independently combine with the carbon to which they are attached and the adjacent

Carbon, forming a double bond, or Kr, Ku, K, and Ka can independently form a double bond with O -I or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from i-th cyclohexane, "g" cyclohex-1-ene, cyclohex-2-ene, 7 cyclohex-3-ene, (Che cyclohexa-1 ,3-diene, cyclohexa-1,4-diene, cyclohexa-1,5-diene, cyclohexa-2,4-diene and cyclohexa-2,5-diene,

IF) and on the condition that 0-7 is cyclohexane, if at least one of -(A) 1-(СВ'В2)-, У, В, В, Вер, име) Vo Ku is linear or branched lower alkenyl (C 2-Cv) or linear or branched lower alkynyl (Co-Cv); 60 of its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective in alleviating the specified condition; a method of treating existing animals for the purpose of ameliorating the condition, wherein the compound is selected for its immunomodulatory, antimalarial, anti-Vogpa virus or anti-hepatitis C, anti-trypanosomal and anti-herpes efficacy, comprising the step of administering to the animal an amount of a compound 65 selected from compounds of the formula AND:

Kk where and oh shcha and! ii vk ih where: - B" means -"(А)п-(СВ 82) 4-МВ ЗВ; - пт, 1 or 2; - А selected from the group containing linear or branched lower alkyl (С.и- Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - B' and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4- Sv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); c - BZ Her KE" are independently selected from the group containing hydrogen, linear or branched lower alkyl (C-4 -Cv), or linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv), or together form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; - VU, Cr, Ka, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower co alkyl(C,-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower M alkynyl (Co-Cv), or in, Cr, Ka; Ki K" can independently combine with the carbon to which they are attached and " an adjacent carbon to form a double bond, or Kr, Ku, K, and K5 can independently form a double bond with ) or U, to which they are attached; IS o) provided that Sh-M-M/-X-y-2 is selected from and - cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, "du cyclohexa-1" -diene, from cyclohexa-1,4-diene, from cyclohexa-1,5-diene, from cyclohexa-2,4-diene and cyclohexa-2,5-diene, 15 and on the condition that 0-7 represents is cyclohexane, if at least one of (А) (СВ), З, В, В», Вр, -1 Ву Ку, is a linear or branched lower alkenyl (С 5-Св) or a linear or branched lower alkynyl ( Co-Cv); o its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective for alleviating the specified condition; a method of treating existing animals to alleviate the condition treated by an MMOBA antagonist,

Sh- selected from the group consisting of excitotoxicity selected from ischemia in stroke, trauma, hypoxia, hypoglycemia, from glaucoma and hepatic encephalopathy, chronic neurodegenerative diseases selected from Alzheimer's disease, vascular dementia, disease

Parkinson's disease, Huntington's disease, multiple sclerosis, lateral, amyotrophic sclerosis,

AIDS neurodegeneration, olivopontocerebellar atrophy, Tourette syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff syndrome and Creutzfeldt-Jakob disease,

F) other disorders related to long-term plastic changes in the central nervous system, selected from chronic pain, drug tolerance, dependence and addiction (for example, opioid, cocaine, benzodiazepine, nicotine, and alcohol), and epilepsy, tardive dyskinesia, and -0ORA-induced dyskinesia, schizophrenia, anxiety, depression, acute pain, elasticity and tinnitus, which includes the step of administering to the animal an amount of a compound selected from the compounds of formula I:

Iv in x, with where: - B" means -"(A)n-(СВ 82) 4-MA ZB; - pt, 1 or 2; - A is selected from the group containing linear or branched lower alkyl (C- i-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - B' and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl (C. 4-Cv), im) to her and : canters her i pis linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); - BZ and E7 are independently selected from the group containing hydrogen , linear or branched lower alkyl(C.4-Cv), (o) linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv), or together form alkylene(Co-C:o) or alkenylene (Co-C:o), or together with M form an optional (C .-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; co zo - B, Cr, Ka, K, and Ke are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.-Cv), linear and or branched lower alkenyl (Со-С1о) and linear or branched lower - alkynyl (Со-Св), or РУ, Кр, Ка, К, and Ке can independently combine with the carbon to which they are attached, and І the neighboring carbon, forming a double bond, or Kr, Ka, K, and Ka can independently form a double bond with U or U to which they are attached; provided that O-M-M/-X-U-7 is selected from cyclohexane, - cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, "cyclohexa-1,3-diene, cyclohex -1,4-diene, - c cyclohexa-1,5-diene, "c cyclohexa-2,4-diene and " cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if, at least one of (А) 1(СВ'В) т, У, В, В, Вр,

Вр Ку, is a linear or branched lower alkenyl (C 5-Cv) or a linear or branched lower - alkynyl (Co-Cv); c its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective in alleviating the specified condition; o a method of treating existing animals with the aim of alleviating the condition treated by an antagonist of the -I 20 5B-HTz receptor, which includes the step of administering to the animal a certain amount of a compound selected from the compounds of formula I:

IR e) ime) 60 b5 n ich

G z k x where: - B" means -"(A)n-(СВ 82) 4-MA ZB; - pt, 1 or 2; - A selected from the group containing linear or branched lower alkyl (C.i -Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - B' and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4 -Cv), c linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); - BZ and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4 -Cv), (o) linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv), or together form alkylene(Co-Cio) or alkenylene(Co-C:iu), or together with M form an optionally (C 4-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; co zo - B, Kr, Ka, K, and K5 are independently selected from groups containing hydrogen, linear or branched lower alkyl (C.-Cv), linear or branched lower a alkenyl (Co-Cv) and linear or branched lower - alkynyl (Co-Cv), or P, Kr, Ka, Ki K5 can independently combine with the carbon to which they are attached and with the adjacent carbon, forming a double bond connection, or Kr, Ka, K, and Ku can independently form a double bond with ) or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene, - c cyclohexa-1,4-diene, and cyclohexa-1,5-diene, ,» cyclohexa-2,4-diene and cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if, at least one of -(А) 1-(СВ'В2)-, У, В, В, Ver, - Vu Ku, represents a linear or branched lower alkenyl(С 5-Св) or a linear or branched lower c alkynyl( Sun-Sun); its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective for alleviating the specified condition; -I 50 a method of treating existing animals in order to alleviate the condition treated by an antagonist of neuronal nicotinic receptors, which includes the step of administering to the animal a certain amount of a compound selected from the compounds of formula I: ime) 60 b5 chi

Y - y at 70 G Y

In, 7 | K

Where: - B" means -"(A)p-(СВ 82) 4-MA ZV; - pt, 1 or 2; - A is selected from the group containing linear or branched lower alkyl (C-i-Cv5 ), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - B and B are independently selected from the group containing hydrogen, linear or branched lower alkyl (C41-Cv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); сч » - ВЗ and Е7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), ( o) linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv), or together form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form an optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; co zo - B, Kr, Ka, K, and Ke independently selected from the group that contains hydrogen, linear or branched lower alkyl (C.-Cv), linear or branched lower alkyl nil(Co-Cv) and linear or branched lower - alkynyl(Co-Cv), or P, Kr, Ka, K, and Ke can independently combine with the carbon to which they are attached and Y with the adjacent carbon, forming a double bond, or Kr, Ku, K, and K5 can independently form a double bond with ) or U to which they are attached; provided that Sh-M-M/-X-y-2 is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene, - c cyclohexa-1,4-diene, and cyclohexa-1,5-diene, ,» cyclohexa-2,4-diene and cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if, at least one of -(А) 1-(СВ'В2)-, У, В, В, Ver, - Vu Ku, represents a linear or branched lower alkenyl(С 5-Св) or a linear or branched lower c alkynyl( Sun-Sun); its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective for alleviating the specified condition; -And 20 a method of treating an existing animal to alleviate a condition treated by a 5-HT antagonist selected from the group consisting of anxiety disorders, depressive disorders, schizophrenia, and related psychoses, disorders associated with drug and alcohol abuse, cognitive disorders, Alzheimer's disease, Parkinson's disease, cerebellar tremor, migraine, appetite disorders, mucositis (IV5) and emesis, which includes the step of administering to the animal an amount of a compound selected from 259 compounds of the formula AND:

F) name) 60 b5

Kk Kk in - us

В Z where: - В" means -(А)п-(СВВ2)4-МАв ЗВ; - pt, 1 or 2; - А is selected from the group containing linear or branched lower alkyl (C4-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - B' and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), c

Linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv); - B3 and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), and 9) linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv) , or together form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl substituted 3-7 --linen azacycloalkane or azacycloalkene; ee) - B, Cr, Ka, K, and Ke independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C.-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl (Co-Cv), or в, Кр, Ку, Ки K" can independently combine with the carbon to which they are attached and " the adjacent carbon, forming a double bond, or Кр, Ка, Ки Ка can independently to form a double bond with ) or U, to which they are attached;

Zo provided that O-M-M/-X-y-7 is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene, o) c cyclohexa-1,4-diene, and » cyclohexa-1,5-diene, cyclohexa-2,4-diene and cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if , at least one of -(А) 1-(СВ'В2)-, У, В, В, Ver, and Во Cr is a linear or branched lower alkenyl(С 2-Св) or a linear or branched lower 1 alkynyl( Sun-Sun); 1" of its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective in alleviating the specified condition; and 20 a method of treating existing animals to alleviate a condition treatable by a neuronal sonicotinic receptor antagonist selected from the group consisting of Tourette syndrome, anxiety disorders, schizophrenia, drug abuse, nicotine abuse, cocaine abuse, dyskinesia (Moghriv

Nipidipyuop, I-SORA-induced), disorders associated with attention deficit hyperactivity disorder (ADHD), the disease

Alzheimer's, Parkinson's disease and pain, which includes the step of administering to the animal an amount of a compound selected from the compounds of formula I:

F) ime) 60 b5 ka in y - y B; where: - B" means -"(A)p-(СВ 82) 4-MA ZV; - pt, 1 or 2; - A selected from the group containing linear or branched lower alkyl (C4 -Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - B' and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4 -St.), village

Linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv); - B3 and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), and 9) linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv) , or together form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl substituted 3-7 --linen azacycloalkane or azacycloalkene; ee) - B, Cr, Ka, K, and Ke independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C.-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl (Co-Cv), or в, Кр, Ку, Ки K" can independently combine with the carbon to which they are attached and " the adjacent carbon, forming a double bond, or Кр, Ка, Ки Ка can independently to form a double bond with ) or U, to which they are attached;

Zo provided that O-M-M/-X-y-7 is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3 -diene, o) c cyclohexa-1,4-diene, "» cyclohexa-1,5-diene, " cyclohexa-2,4-diene and cyclohexa-2,5-diene, and provided that 0-7 represents is cyclohexane, if at least one of -(A) 1-(СВ'В2)-, В, В, В, Ver, and Vo Cr is a linear or branched lower alkenyl (С 2-Св) or a linear or branched lower 1 alkynyl (Co-Cv); 1" of its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective in alleviating the specified condition; - and 20 use of the compound of formula I, which is determined in connection with the previous methods, and its optical isomers and with pharmaceutically acceptable additive salts of acids or bases in the production of a medicinal product for use in any such method; and a pharmaceutical composition containing a compound selected from compounds of formula I:

F) name) 60 b5 p ee and shcha

M

- h o G

Erolinia ram y ka ke where: - B" means -"(A)p-(СВ 82) 4-МВ ЗВ; - pt, 1 or 2; - A selected from the group containing linear or branched lower alkyl (C- and -C5), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); c - B and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl (C4- Sv), o linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); - BZ and KE" are independently selected from the group containing hydrogen, linear or branched lower alkyl (C4-Cv ), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv), or together with co z form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form an optional (C .-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; in. - VE? independently selected from the group consisting of linear or branched lower alkyl(Ci-Cv), linear or "E branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv), or B? combines with the carbon to which it is attached and the neighboring carbon, forming a double bond; o - Cr, Ku, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl (C--Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co- Sv), or Kr, Ka, K, and KC can independently combine with the carbon to which they are attached and the neighboring carbon, forming a double bond, or Kr, Ku, K, and K5 can independently form a double bond connection with ) or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from - c cyclohexane, c cyclohex-1-ene, "» cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene , -I cyclohexa-1,4-diene, cyclohexa-1,5-diene, other cyclohexa-2,4-diene and "g" cyclohexa-2,5-diene, and provided that at least one of Ker and Ka is not hydrogen, and at least one of K, and K. is not hydrogen, provided that 0-7 is cyclohexane, if at least one of -(А) 1-(СВ В) n , Kr, Ko, Ki K»5 represents

IR e) is linear or branched lower alkenyl (Co-Cv) or linear or branched lower alkynyl (Co-Cv); and its optical isomers and pharmaceutically acceptable addition salts of acids or bases, in combination with one or more pharmaceutically acceptable diluents, excipients and/or

CARRIERS

DETAILED DESCRIPTION OF THE INVENTION

IF) The following details and detailed examples are provided for illustrative purposes only and are not restrictive. name) Scheme: examples 1 and 2 60 b5

Scheme: examples 112 on soo y (vozROYUENsoovi || An, (0 possm man nn nyn in schi nnnyvnnnnnnnia and - a

Place 2. Xylol, A

Ma Me Me Me Me 70 Me Me Me 1 2 Me. Me and Masn, DMSO Y and 1. 15 . iy Dd sko me, Ma so

Me 2NA BO is me tgF

Me 4 Ma me me 5 1. nAN, nimetnya pnya r I se 2. NS

Me Mo Me o

Ma Me in me ,. Me c

Example 1 h-

3,3,5,5-tetramethyl-1-vinylcyclohexanamine hydrochloride (5) a) Ethyl 2-(3,3,5,5-tetramethylcyclohexylidene)acetate (2) C

To a stirred solution of triethylphosphonoacetate (49.32g, 222mmol) in anhydrous THF (180ml) under an argon atmosphere was added Mann (8.8g, 222mmol, 6090 suspension in mineral oil) in small portions while cooling with ice water. Stirring is continued for an hour. at room temperature, then add a solution of 3,3,5,5-tetramethylcyclohexanone (30.85 g, 200 mmol) over 1 hour. and the resulting mixture is refluxed for 22 hours. Then it is poured onto ice (400 g) and the product is extracted with diethyl ether (4x1500 ml), the extracts are dried over M950). After evaporation of the solvent in vacuum, oily « 70 The residue is distilled at 1452C (11 mm Hg), obtaining 36.8 g (8696) 2 in the form of oil. "H-NMR (SOCI3, TM), w-in m.p.: 0.96 and 0.98 (total 12Н, both с, 3,5-СН»3); 1.27 (ЗН, т, CH3-ethyl); 1.33 (2H, m, 4-CH»); 1.95 and 2.65 (total with AN, both c, 2,6-CH»); 4.14 (2H, sq, СНо-ethyl) and 5.69 (1Н, с, -Н). :з» 5) 2-(3,3,5,5-tetramethylcyclohexylidene)ethanol (3)

A solution of acetate 2 (3.2 g, 1 mmol) in ether (200 ml) was added dropwise to a stirred solution of GiAIN (1.7 g, 45 mmol) in anhydrous ether (bOml) while cooling with ice water. Stirring continues -1 for an hour. and the remaining HYAIN is decomposed with water. The aqueous layer is separated and extracted twice with ether (3 mL). The combined extracts are washed with saturated salt solution (ppm) and dried over M950.4. After concentration in a vacuum, the oily residue is purified by distillation in a Kideigoig apparatus with a short nozzle (150-1702C, 11 mm Hg), obtaining Z (2.3g, 89905) in the form of oil. "NYAM (SOSIZ, TM5), m.p.: 0.92 (6H, s, Z, 5-SNU); 1.10 (1H, shir.s, ОН); 1.28 (2H, s, 4 -CH»); 1.87 and 1.94 (total 4H, both c, 2,6-CH»); 4.16 (2H, d, 7Hz, 7CH»O) and 5.50 (1H, t , 7Hz, -С-Н). со с) 2,2,2-trichloro-M-(3,3,5,5-tetramethyl-1-vinylcyclohexyl)acetamide (4)

Man (0.22g of 5595 dispersion in mineral oil (0.22mmol)) is added to a solution of alcohol C (0.8g, 4.7mmol) in diethyl ether (Hml). The reaction mixture is cooled to -109C and a solution of trichloroacetonitrile (0.68g, 4./mmol) in diethyl ether (3ml) is added dropwise. The solution is allowed to warm to room temperature and the solvent is evaporated. Pentane (8 ml) containing methanol (0.018 ml) is added to the residue. i) The resulting mixture is filtered through a layer of celite and evaporated. The remaining oil is dissolved in xylene (10 ml) and refluxed for 1 hour. The main amount of xylene was distilled off under reduced pressure (1 mm Hg) and the residue was purified by flash chromatography on silica gel (hexane, 600 hexane-ethyl acetate, 10:11), obtaining 4 (0.98 g, 6690) as an oil. TN-NMR (SOS, TM5), m.p.: 0.95 (BN, c, 3,5-SNU); 1.18 (BN, c, 3.5-CH3); 1.1-1.5 (2H, m, 4-CH"); 1.32 (2Н, d, 15Hz, 2,6-СН»); 2.15 (2Н, d, 15Hz, 2,6-СН»); 5.08 (1H, d, 11Hz, CH"); 5.13 (1H, d, 18Hz, CH"); 5.85 (1H, dd, 18 and 11Hz, -HO-) and 6.7 (IN, shir.s, MH). a) 3,3,5,5-tetramethyl-1-vinylcyclohexanamine hydrochloride (5)

A mixture of amide 4 (0.32g, 1immol) with Masson powder (0.4g, TOmmol) in DMSO (3ml) was stirred for 7 days at room temperature. The reaction mixture was diluted with NaOH (20 mL) and stirred overnight at room temperature. The product is extracted with hexane (3x1Oml). The combined extracts are washed with saturated salt solution

(20 ml), dried over Masn and filtered through a layer of celite. 4M HCI in anhydrous diethyl ether (0.5 ml) is added to the resulting solution and the solvent is evaporated. The residue was treated with acetonitrile (1 mL), and the precipitate was filtered off and dried over RoOB in vacuo to afford 5 (0.12 g, 53905) as a colorless solid. "H-NMR (SOSIZ, TM5), mp: 0.98 and 1.01 (total 12Н, both с, 3.5-СН3); 1.19 and 1.29 (total 2Н, both d, 14Hz, 4-CH"); 1.62 (2H, d, 13.5Hz, 2,6-CH"); 1.72 (2H, shir.s, H2"O); 2.16 (2H, d , 13.5Hz, 2,6-CH"); 5.46 and 5.73 (2H, both d, 18 and 11Hz, CH"); 6.16 (1H, dd, 18 and 11Hz, CH) and 8 ,24 (ZN, shir.s, MNz 7).

Example 2

3,3,5-pentamethyl-1-vinylcyclohexylamine hydrochloride (7) a) Methyl 3,3,5,5-tetramethyl-1-vinylcyclohexylcarbamate (6) A mixture of amine hydrochloride 5 (0.25g, 1.2mmol) and

MaSo" (0.73 g, b.9 mmol) in THF (bml) is stirred at room temperature for 1 hour. Methyl chloroformate (0.277, 345 mmol) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture is diluted with diethyl ether (200 ml), filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 6 (0.24 g, 75 8795) as a colorless solid with m.p. 61-632C. "H-NMR (SOCI3, TM), m.p.: 0.92 and 1.15 (total 12Н, both с, 3.5-СН»3); 1.00-1.40 (4Н, m, 4-CH" and 2,6-CH); 2.00 (2H, d, 14Hz, 2,6-CH); 3.62 (ZH, s, SNUM); 4.72 (IN, shir.s, МН); 5.00 and 5.06 (total 2Н, both d, 10.5 and 17Hz, CH") and 5.83 (1Н, dd, 10.5 and 17Hz, CH). 5) HydrochloridkK,3, 3,5,5-pentamethyl-1-vinylcyclohexylamine (7)

A mixture of TSAIIIN; (0.28g, 7.4mmol) and carbamate 6 (0.22g, 0.92mmol) in THF (22ml) are refluxed for 12h. Then it is cooled in an ice bath and water (2 Oml) is added drop by drop.

The obtained suspension is extracted with hexane (3x2Oml) and the combined extracts are washed with saturated salt solution (20ml). The extract is dried over Mahon, filtered and treated with a 2.4 M solution of HCI in diethyl ether (ml).

The resulting suspension is evaporated to dryness. The residue is treated with diethyl ether (1 mL) and acetonitrile (1 mL). The precipitate was filtered and dried under vacuum over R»Ob, obtaining 7 (0.11 g, 52905) as a colorless solid with 29. "H-NMR (SOSIZ, TM), m.p.: 1.00 and 1.02 (total 12Н, both c, 3,5-CHnaz); 1.23 and 1.32 (total (U 2Н, both d, 15Hz, 4-CH"); 1.72 (2H, d, 13Hz, 2,6-CH); 2.15 (2H, d, 13Hz, 2,6-CH); 2.45 (ЗН, t, 5Hz, SNzZM); 5.64 and 5.69 (total 2Н, both d, 11 and 17Hz, СН»); 5.98 (1Н, dd, 11 and 17Hz, СН) and 9.30 (2Н, shir.s, MNz 7).

Scheme: examples C and 4 | so о Scheme: examples 3 14 вх вх "I

IS)

AlilMeVg, he m.

TMM, Ve, nni pn tnih and en night chans fr

Me Seya,

Me

Me Mo Me Me s ! .

I» M, Y M, sl Me Me

Me Mo Ma Ma t» 9 Ki: - 50 so AN, NO IN, that 2, SO 2.NOi, E.O in

F) and Mine nnune 60

Me M y me Me me " m b5

Example C

Hydrochloride of 1-allyl-3,3,5,5-tetramethylcyclohexanamine (11) a) 1-allyl-3,3,5,5-tetramethylcyclohexanol (8)

A solution of 3,3,5,5-tetramethylcyclohexanone (3.8b6g, 25mmol) in anhydrous ether (20ml) was added dropwise to a 1M stirred ethereal solution of allylmagnesium bromide (bOml, bbmmol). The mixture is stirred for an hour. at ambient temperature and refluxed for 1 hr. Then it is cooled with ice water and carefully ground in saturated aqueous M.A.S.I. (40 ml). The organic layer is separated and washed with water and saturated salt solution. After drying over anhydrous Mo5O), the solution is concentrated in a vacuum. Perform fractional distillation of the residue under reduced pressure, obtaining 3.5 g (7290) 8 from 70 tons of boiling water. 98-100C/12mm Hg. Art. "H-NMR (SOCI3, TM8), m.p.: 0.88 (6H, c, 3,5-CHz); 1.20 (6H, c, 3, 5-CHz); 0.95-1 .60 (6Н, m, 2,4,6-СН»); 2.15 (2Н, d, 7.5Hz, СНЬсС-); 4.95-5.30 (2Н, m, СН») and 5 .65-6.20 (1H, m, CH).

B) 1-allyl-1-azido-3,3,5,5-tetramethylcyclohexane (9) and 1-methyl-2-(3,3,5,5-tetramethylcyclohexylidene)ethylazide (10)

75 g of azidotrimethylsilane (12 mmol) was added to a solution of cyclohexanol 8 (1.96 g, 1 mmol) in anhydrous benzene (20 ml) under an argon atmosphere. To this cooled (523) solution, BE3000 (12 mmol) was slowly added using a syringe over 20 min. The mixture is stirred for two hours, then slowly water is added. The organic layer is separated and washed with saturated aqueous Manso with and saturated salt solution and dried over Mo5O.

Filtration and evaporation of the solvent while maintaining the temperature below 25 C give oil, which is isolated by column chromatography on silica gel (light petroleum ether). The fraction with KIT 0.85 (hexane) is collected. Evaporation of the solvent gave 9 as a colorless oil (0.26g, 11.795). "H-NMR (SOCI3, TM5), m.p.: 0.89 (6Н, s, 3,5-CHzed); 0.90 (1Н, d, 14Гу, 4-СНах); 1.05 (2Н . 14Hz, 2,6-SNed), 2.29 (2H, d, 7Hz, СНоС-); 4.95-5.25 (2Н, m, СН") and 5.65-6.15 (IN, m , -CH).

Evaporation of an additional fraction (CT 0.65 (hexane)) gives 0.425 g (20.395) of azide 10 as a colorless solid. "H-NMR (SOCI5, TM5), molecular weight: 0.91 (6Н, с), 0.94 (ЗН, с) and 0.96 (ЗН, с, 3,5-СНу); 1, 23 (ZH, d, 6.5 Hz, 1-CH3); 1.26 o (2H, c, 4-CH»); 1.89 (2H, c) and 1.96 (2H, c, 2.6 -CH"); 4.31 (1H, dkw, 6.5 and 9.5Hz, 1-CH) and 5.21 (1H, dm, 9.5Hz, CH). c) Hydrochloride 1-allyl-3, 3,5,5-tetramethylcyclohexanamine (11) A solution of azide 9 (0.221 g, 1.0 mmol) in anhydrous ether (4 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (0.152 g, 4 mmol) in ether (1 mL) 10 min. The mixture is stirred for 4 hours, then treated with 2095 aqueous Mahon (8 ml). The aqueous layer is separated and extracted with diethyl ether (2 x 15 ml). The combined organic extracts are washed with saturated sodium chloride solution and dried over Mahon. The filtered solution is treated with anhydrous solution of NH! in diethyl ether and evaporated. Anhydrous diethyl ether is added to the solid residue, filtered and washed with anhydrous ether, obtaining 11 (0.105 g, 4795) as a colorless solid. "H-NMR (SOCI3, TM5), .ch.: 1.03 (BN, p. 3 ,5-SNzed); 1.06 (6H, c, 3,5-CHz); 1.29 (2Н, с, 4-СН»); 1.63 (2Н, d, 13Гу, 2,6-СНах); 1.80 (2H, d, m 13Hz, 2,6-SNed), 2.71 (2H, d, 7Hz, CH2O); 5.10-5.40 (2H, m, "CH"2); 5.75-6.25 (1H, m, CH) and 8.25 (ZH, shir.s, MHz").

Example 4

Hydrochloride 1-(3,3,5,5-tetramethylcyclohexylidene)-2-propanamine (24)

A solution of 1-methyl-2-(3,3,5,5-tetramethylcyclohexylidene)ethylazide (10) (0.33g, 1.5mmol) in anhydrous diethyl ether (4ml) was added dropwise to a stirred suspension of lithium aluminum hydride ( 0.152 g, -about 4 mmol) in ether (15 ml) in 10 min. This mixture is stirred for 4 hours, then it is treated with 20956 aqueous Mans (dml). The aqueous layer is extracted with ether (2 x 1 bml). The organic extracts are combined, washed with saturated salt solution and dried over NaOH. The filtered solution is treated with an anhydrous solution of NSI in ether and evaporated in a vacuum. Add anhydrous ether to the solid residue, filter and wash with anhydrous ether to give 24 (0.18g, 54965) as a colorless solid. TN-NMR (SOSIZ, TM), m.p.: 0.89 -i (6Н, с), 0.92 (ЗН, с) and 0.98 (ЗН, с, 3, 5-СН»); 1.27 (2Н, с, 4-СН»); 1.47 (ZN, d, 6.5 Hz, 3-SNUz); 1.84 (1H, d, 13.5Hz, 2-CH); 1.87 (2H, c, 6-CH"), 2.06 (IN, d, 13.5Hz, 2-CH); 4.17 (IN, DC, 6.5 and 9.5Hz, 2-CH); 5.35 (1H, d, i-th 9.5Hz, CH) and 8.25 (ZH, shir.s, MNz"). t» Scheme: examples 5,6 and 7 - 50

IR e)

F) name) 60 b5

Scheme: examples 5,617

Me o Pperidin 14. DAON

Me me RN g.s»"SNeSN.Vg, p

Ma to 1 12 2. NS, BO 1. ASON U GPropargil (Ve, 7p

Kk E

With 2. NS, IVF d

Me is also guilty

Me Me

Me k-t Me pl

Me ZNO Me "NO 13 en, 4 Me 15

Example 5 sem

Hydrochloride 1-(1-allyl-3,3,5,5-tetramethylcyclohexyl)piperidine (13) o a) 1-(3,3,5,5-tetramethyl-1-cyclohexenyl-1)piperidine (12)

Obtained by condensation of piperidine (1.2 equivalents) and 3,3,5,5-tetramethylcyclohexanone when heated in benzene with azeotropic removal of water. The crude product is obtained by removing the starting substances under vacuum distillation conditions (100C/10mm Hg). Amber oil. "H-NMR (SOSIz, TM), m.p.: 0.94 (BN, c) and co 0.97 (6H, c, 3, 5-SNU); 1.25 (2H, c, 4- CH»); 1.40-1.70 (6H, m, piperidine 3,4,5-CH»); 1.76 (2H, c, 6-СНо); 2.60-2.85 im (DAN , m, piperidine 2,6-CH»5) and 4.40 (1Н, с, CH). 5) 1-(1-allyl-3,3,5,5-tetramethylcyclohexyl)piperidine hydrochloride (13) "

Acetic acid (0.675g, 11.25mmol) was added to a solution of enamine 12 (2.1g, ummol) in THF (20ml). The mixture is stirred for 5 min. and add zinc powder (0.74g, 11.25mMgA). Then the solution is added drop by drop

of allyl bromide (1.63 g, 13.5 mmol) in THF (Bml) and the mixture is stirred at ambient temperature. within 6 hours Aqueous NaCl(CO)) is added and the resulting mixture is extracted with ether. The extract is washed with a saturated salt solution, dried over anhydrous Mo5O), and concentrated in a vacuum. The residue is isolated by column chromatography on silica gel (hexane, 595 ЕХОАс in hexane). The fraction with CT 0.85 (hexane-E(OAc, 13:2) is collected, evaporated and treated with an anhydrous solution of NCI in ether. The precipitate is filtered and washed with a mixture of hexane-EOds, obtaining 13 (0.79g, 29965) as a colorless of a solid substance. "H-NMR (SOS, TM5), m.p.: C s 1.07 (6H, s, 3,5-CHzed), 1.10 (6H, s, 3, 5-CHzach); 1.34 (1H, d, 12.2Hu) and 1.45 (1H, d, 12.2Hu, 4-CH"); 1.70-1.95 (6vH, z" m, 2,6-CH and piperidine 3,5-CH, 4-CH»o-); 2.37 (2H, d, 13.4HC, 2, 6-CHno); 2.40-2.70 (2H, m, piperidine 3, 5-CH); 2.16 (2H, d, 7.2Hz, CHlC-); 2.75-3.00 (2H, m, piperidine 2,6-CH); 3.64 (2H, d, 11 ,6Hz, piperidine 2,6-CH); 5.13 (IN, d, 9.6Gu) and 5.24 (1H, d, 17.8Hz, CH); 5.85-6.15 (1H, m, CH) and 10.72 (1Н, шир.с, МН).

Example 6

1-I(3,3,5,5-tetramethyl-1-(3-methyl-2-butenyl)cyclohexyl/|-piperidine hydrochloride (14)) is obtained from piperidine 12 according to the procedure for compound 13 (example 5, B), using 4-bromo-2-methyl-2-butene instead of allyl bromide. Yield: 2095. "H-NMR (SOCI3, TM), m.p.: 1.07 and 1.08 (total 12H, e both c, 3,5-CH»Y), 1.32 and 1.44 (2H, both d, 14.2Hz, 2-CH»5); 1.69 and 1.76 (6H, both c, "C (CH»3)»); 1.68-1 96 -I 50 (4H, m, 3,5-CH and 4-CH»); 1.84 (2H, d, 13.4Hz, 2, 6 -CHNax); 2.91 (2H, d, 13.4Hz, T, 6-CHn); 2.40-2.80 (4H, m, Sh(CH)", so 3.5-CH); 2 ... (1H, width s, MN).

Example 7

1-I(3,3,5,5-tetramethyl-1-(2-propynyl)ucyclohexyl|piperidine) hydrochloride (15)

Obtained from piperidine 12 according to the procedure for compound 13 (example 5, 5), using 3-bromopropyne instead of allyl bromide. Yield: 6905. TN-NMR (SOSIZ, TM), m.p.: 1.07 (6Н, с, 3, 5-СНзед), 1.11 (6Н, с, 3, 5-СНзах);

HF) 1.23 and 1.44 (total 2H, both d, 14.3Hz, 2-CH»o); 1.75-2.00 (4H, m, piperidine 3,5-CH, 4-CH"); 1.91 (2Н, д, г) 13.2Hz, 2, 6-СНах); 2.28 (1H, c, NSS); 2.34 (2H, d, 13.2Gu, 2, 6-SNed); 2.40-2.70 (2H, m, piperidine 3,5-CH); 2.81 (2H, c, SNSS); 2.85-3.10 (2H, m, piperidine 2,6-CH); 3.69 (2H, d, 10.2Hz, piperidine 2,6-CH) and 11.12 (1H, shir.s, MH). in Scheme: examples in 9 b5

Scheme: examples 819 and 7

Mel ON en,s(oB, me meon, EON

Me Catalyst Me sovi A

SNSOON

Me Z Me 416 ve 1. OSS, NBU in y yin and Y tyna nn

Me soon 2 MnyNoO Me soOmn,

Me 47 Me 48 1. ORRA, SM, | 2. aq. NSI benzene, boiling with. | Z.IMeSM, boiling with 1.ts6InN. pF reverse reflux refrigerator Zholodilynk 2 on, o

Me and sch

Me and mn, Nei Me Go)

Me

Me "/a with Me 19 p

Example 8

Hydrochloride 2-(3,3,5,5-tetramethyl-1-vinylcyclohexyl)ethanamine (19) a) Ethyl 2-(3,3,5,5-tetramethyl-1-vinylcyclohexyl)acetate (16) c

A mixture of triethylorthoacetate (18.b6ml, 102mmol), 2-(3,3,5,5-tetramethylcyclohexylidene)ethanol (3) (4.63g, (3,254mmol)) and propionic acid (0.19ml, 2.5mmol) is heated at 1459 for 1 hour During the reaction with

Ethanol is distilled from the mixture. The reaction mixture is cooled and poured into water (10O0ml). The aqueous phase is extracted with hexane (2x5Oml) and the combined organic phases are washed with 596 aqueous KNZO (50ml) and saturated salt solution (5Oml). The extract is dried over Moa53O), filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether and light petroleum ether-ethyl acetate, 100:2) to give 16 (4.64 g, 7396) as an oil. "H-NMR (SOCI3, TM), m.p.: 0.91 (6H, c, 3,5-CH»U); 1.01 (6H, c, 3,5-CH»a); with 1.23 (ZH, t, 7Hz, ethyl CH") 1.00-1.30 (4H, m, 4-CH" and 2,6-CH); 1.86 (2H, d, 13Hz, 2, 6-CH); 2.22 (2H, s, CHNS-O); 4.08 s (2H, qu, 7Hz, ethyl CH»); 5.06 and 5.07 (total 2H, both d, 11 and 17.5Hz, CH") and 5.95 (1H, dd, 11 and 17.5Hz, -CH:). :z» 5) 2-(3,3,5,5-tetramethyl-1-vinylcyclohexyl)acetate acid (17)

A solution of Mahon (1.03 g, 25.8 mmol) and acetate 16 (1.3 g, 5.15 mmol) in methanol (2 bml) is refluxed for 15 h. The mixture is cooled to room temperature and poured into water (10 Oml). The aqueous -1 phase is acidified with concentrated aqueous HCl and extracted with hexane (3 x 30 ml). The combined organic phases are washed with a saturated salt solution, dried over CaCl, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 17 (0.7 g, 7195) as a colorless solid with m.p. 92-9496, TN-NMR (SOCI3, TM5), m.p.: 0.92 (BN, c, 3,5-CH"); 501.02 (BN, c, 3,5-CH"); 1.00-1.30 (4H, m, 4-CH» and 2,6-CH); 1.90 (2H, d, 14Gu, 2,6-CH); 2.27 (2H, c, SNOS-O);, 511th - 5.13 (total 2H, both d, 11 and 18Hz, CH"); 5.99 (1H, dd, 18 and 11 Hz, CH) and 10.80 (1H, shir.s, COOH). so c) 2-(3,3,5,5-tetramethyl-1-vinylcyclohexyl)acetamide (18)

M-hydroxysuccinimide (0.25g, 2.2mmol) and M,M'-dicyclohexylcarbodiimide (0.45g, 2.2mmol) were added to a solution of cyclohexylacetic acid 17 (0.45g, 2mmol) in THF (ml). The mixture is stirred for 18 hours. at room temperature and cooled in an ice bath. Add 2575 aqueous MNAON (2 ml) in one portion and stir the mixture at room temperature for 2 hours. The precipitate is filtered and washed with diethyl

F) ether (ZOml). The organic phase of the filtrate is separated and washed with 595 ml of aqueous KNZO; (1 Oml) and a saturated salt solution. The extract is dried over Mao5O), filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, from 4:1 to 1:1), obtaining 18 (0.34 g, b.o. 7695) as a colorless solid with m.p. 44-46960. TN-NMR (SOS, TM5), m.p.: 0.91 (6Н, с, 3,5-СН»); 1.02 (6Н, с, 3,5-СН»); 1.00-1.30 (4H, m, 4-CH» and 2,6-CH); 1.85 (2H, d, 14Hz, 2,6-CH); 2.13 (2H, c, SNHS-O); 5.18 and 5.19 (only 2H, both d, 18 and 11Hz, CH"); 5.40 and 5.60 (total 2H, both shir.s, МН») and 6.03 (1H, dd, 18 | and 11Hz, CH). a) 2-(3,3,5,5-tetramethyl-1-vinylcyclohexyl)ethanamine hydrochloride (19) 65 Mixture of AN; (0.41g, 1Tmmol) and amide 18 (0.30g, 14mmol) in THF (18ml) were refluxed for 17h. Then it is cooled in an ice bath and water (ZOml) is added drop by drop.

The resulting suspension is extracted with hexane (300 ml) and the combined organic phases are washed with a saturated salt solution. The extract is dried over Mahon, filtered and concentrated to a volume of -10 ml. A 4.8M solution of NOSI in diethyl ether (Iml) is added and the resulting suspension is evaporated to dryness. The residue was treated with acetonitrile (5 mL), the precipitate was filtered off and dried in vacuo over NaOH to give 19 (0.16 g, 5090) as a colorless solid. "H-NMR (SOSIZ, TM5), m.p.: 0.89 (6Н, с, 3,5-СНа); 1.02 (6Н, с, 3,5-СНаз); 0.90-1 ... ); 5.77 (1H, dd, 18 and 11 Hz, CH) and 8.10 (ZH, shir.s, MHz 7).

Example 9

3-(3,3,5,5-tetramethylcyclohexylidene)propanamine hydrochloride (32)

Triethylamine (0.25ml, 1.7bmmol) and diphenylphosphorylazide (0.38ml, 1.7bmmol) were added to a solution of acid 17 (0.36g, 1.bmmol) in benzene (bml). The mixture is refluxed for 2 hours, cooled to room temperature and evaporated to dryness. Add cold (7523) concentrated aqueous NSI (Zml) to the residue. The resulting mixture is stirred at room temperature for 18 hours. and make strongly alkaline, 72 adding 1095 aqueous MaoN. Hexane (20 ml) was added to the mixture and both phases were filtered. The sediment is washed with hexane (2x5ml) and water (2xbml). The organic phase of the filtrate is separated. The aqueous phase is washed with hexane (2 x 10 ml). The combined organic phases are washed with a saturated salt solution (1 Oml), dried over NaCl and filtered.

Add 4.8 M solution of NS! in diethyl ether (ml) and the resulting suspension is evaporated. The residue was recrystallized from acetonitrile and dried in vacuo over RoOb5 to give 32 (0.1 g, 43905) as a colorless solid. TN-YAMe (SOS, TM5), m.p.: 0.90 and 0.92 (total 12H, both c, cyclohexane-3,5-CH U); 1.23 (2H, c, cyclohexane-4-CH"); 1.86 and 1.92 (total 4H, both c, cyclohexane-2,6-CH»5); 2.49 (2H, square, 7Hz, propanamine-2-CH); 2.98 (2H, t, 7Hz, propanamine-1-CH»0); 5.15 (1Н, т, 7Hz, -СН-) and 8.30 (ЗН, шир. с, МНз 7). | ch 25 Scheme: examples 10 and 11. (8)

Scheme: examples 0111 her in so » Me that BK i-Й Me FfyAnN. Sk

Me OO syu Me smt te

And "

Me 4 Man, yF Me zb ven 2na, vo yu zv vu NN, b) KeMe 21 v-Me Kk «

Me - » 40 «Dn na - s i »

I Me zaken 23 K-Me their Example 10 1 Hydrochloride 2-(3,3,5,5-tetramethylcyclohexylidene)ethanamine (22) i» a) 3,3,5,5-tetramethylcyclohexylideneacetonitrile (20) 6095 Man dispersion in mineral of oil (0.96g, 24mmol) was added to a solution of diethylcyanomethylphosphonate -i 20 (4.25g, 24mmol) in THF (30ml) while cooling with ice water. The mixture is stirred ZOkhv. and add dropwise a solution of 3,3,5,5-tetramethylcyclohexanone (3.08 g, 200 mmol) in THF (10 ml). The cooling bath is removed and the mixture is stirred at room temperature for 72 hours. Pour it into ice water (100ml) and extract with diethyl ether (3x50ml). The combined organic phases are washed with saturated salt solution, dried over Mazo, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 20 (2.38g, 7195) as a colorless (F) oil. "H-NMR (SOCI3, TM5), m.p.: 0.97 and 1.01 (total 12H, both c, 35-CH»y); 1.36 (2H, c, 4-CH»o) ; 2.01 (2H, s,

He 2'-CH"); 2.26 (2H, c, 6-CH") and 5.14 (1H, c, -CH). 5) Hydrochloride of 2-(3,3,5,5-tetramethylcyclohexylidene)ethanamine (22) 60 A suspension of HYAIN (0.68 g, 18 mmol) in diethyl ether (30 ml) is cooled in an ice bath and a 1 M solution of 7 pSi" in diethyl ether is added (duml, Ummol). The resulting mixture is stirred for 15 minutes. and add dropwise a solution of nitrile 20 (1 g, mmol) in diethyl ether (3 mL), maintaining the temperature at 0-59. Then the ice bath is removed and the mixture is stirred at room temperature for 24 hours. Add water (ZOml) and 2095 aqueous Mahon (20ml) while cooling in an ice bath. The aqueous phase is extracted with diethyl ether 65 (x50ml). The combined organic phases are washed with saturated salt solution (50 ml), dried over Mahon, filtered and evaporated. The residue is purified by distillation in a Kideigoig apparatus with a short nozzle at 1602C/20 mm Hg.

The distillate is diluted with diethyl ether and a 4.8M solution of HCI in diethyl ether (3ml) is added. The resulting precipitate was filtered off, washed with diethyl ether (3x5ml) and dried under vacuum over Mahon, obtaining 22 as a colorless solid. TN-NMR (SOSIZ, TM5), m.p.: 0.91 and 0.92 (total 12H, both c, 3, 5-CH"); 51.28 (2Н, с, 4-СН»); 1.89 and 1.93 (total 4Н, both с, 2,6-СН»); 3.62 (2H, d, 7Hz, SNOM); 5.41 (1H, t, 7Hz, -С-СН) and 8.3 (ЗН, шир.с, МНз").

Example 11

2-(3,3,5,5-tetramethylcyclohexylidene)propanamine hydrochloride (23) a) 2-(3,3,5,5-tetramethylcyclohexylidene)propionitrile (21)

Obtained according to the method for compound 20 (example 10, a), using diethyl (1-cyanoethyl) phosphonate. Nitrile 21 is obtained as a colorless oil with a yield of 4195. "H-NMR (SOS,

ТМ5), m.p.: 0.96 and 1.00 (total 12Н, both с, cyclohexane-3,5-CH3); 1.34 (12H, c, cyclohexane-4-CH"); 1.91 (ZH, c, propionitrile-3-CH"); 2.04 and 2.28 (total AN, both c, cyclohexane-2,6-CH"). 5) 2-(3,3,5,5-tetramethylcyclohexylidene)propanamine hydrochloride (23)

It is obtained from nitrile 21 according to the method for compound 22 (example 10, b).

Amine hydrochloride 23 is obtained as a colorless solid. "H-NMR (SOSIZ, TM), m.p.: 0.92 and 0.93 (total 12H, both c, cyclohexane-3,5-CHa3); 1.27 (2H, c, cyclohexane-4- СНо); 1.89 (ЗН, с, propanamine-3-СН с); 1.99 and 2.01 (total 4Н, both с, cyclohexane-2,6-СН»); 3.64 (2Н, shr .s, propanamine-1-CH»5) and 8.40 (ZH, shir.s, MHz 7).

Scheme: example 12

Scheme: example 12 p

With (o) o on

Alilimovg, BO TMM, VEGO, co

It is the ladies

Me

Me Me M « 25 Me 26 a

I have

What is it and -

M, "NOI 1lAN, VO | Mn, « " - 7 2.NSI, o "with Me Ma " Me Me Me Me - - os Example 12

Hydrochloride (E,2)-1-(3,3-diethyl-5,5-dimethylcyclohexylidene)-2-propanamine (28) and a) 1-allyl-3,3-diethyl-5,5-dimethylcyclohexanol (26) -I 20 A solution of 3,3-diethyl-5,5-dimethylcyclohexanone (25) (1.47g, 8.0bmmol) in anhydrous ether (bml) was added dropwise to a 1M stirred ethereal solution of allylmagnesium bromide (20ml, 20mmol). This mixture is stirred for an hour. at ambient temperature and refluxed for 1 hr. Then it is cooled with ice water and treated with saturated aqueous MnCl (4 Oml).

The organic layer is separated and washed with water and saturated salt solution. After drying over anhydrous

Mao), the solution is concentrated in a vacuum. The residue is purified by column chromatography on silica gel

GF) (light petroleum ether). The fraction with CI 0.7 (hexane:'E(Ac, 13:2) is collected. Evaporation of the solvent gives 26

GF (1.35 g, 7495) in the form of colorless oil. TN-NMR (SOSIZ, TM5), m.p.: 0.74 (6H, t, 7/Hz, 2CH» ethyl); 0.88 (ZH, c, 5-CHzed); 1.19 (ZN, c, 5-CHzach); 0.80-2.05 (TON, m, 2,4,6-CH» and 2CH» ethyl); 2.14 (2H, d, 7Hz, SNOW); 4.95-5.30 (2H, m, CH") and 5.65-6.20 (1H, m, CH). 60 B) (E,2)-1-methyl-2-(3,3-diethyl-5,5-dimethylcyclohexylidene)ethylazide (27) Obtained from cyclohexanol 26 according to the method for compounds 9 and 10 (example 3, B) . Azide 27 is obtained as a colorless oil with a yield of 1595. H-NMR (СОС153, TM5), m.p.: 0.73 and 0.74 (total 6Н, both t, 7Hz, 2СНu ethyl); 0.91, 0.94 and 0.97 (total 6Н, all с, 5, 5-CH3); 1.10-1.45 (4H, m, 65 2CH» ethyl); 1.22 (ZH, d, 6.5Hz, 1-CH"); 1.26 (2Н, с, 7-СН»); 1.89 (2H, c) and 1.97 (2H, m, 21, 6-CH"); 4.08-4.48 (W, m, 1-CH) and 5.18 (W, dm, 9.5Hz, CH).

c) Hydrochloride (E,2)-1-(3,3-diethyl-5,5-dimethylcyclohexylidene)-2-propanamine (28)

Obtained from azide 27 according to the procedure for compound 24 (example 4). The hydrochloride of amine 28 is obtained as a colorless solid with a yield of 16905. TN-NMR (SOSIS, TM5), m.p.: 0.72 (6Н, shr.t, 7Hz, 2СНУ3 ethyl), 0.90, 0.92 and 0.98 (total BN, all c, 5, 5-CH»z); 1.25 (6H, m, 4-CH» and 2CH» ethyl); 1.47 (ZN, d, 6.5Hz, 2-SNU"); 1.70-2.25 (2H, width AB square, 13 Hz, 2-CH"); 1.87 (2H, c, 6-CH"), 4.18 (1H, m, 2-CH); 5.34 (IN, lat.d, 9.5Hz, SN) and 8.38 (ZN, lat.s, MNz").

Scheme: example 13

Scheme: example 13 ii

Me Me in Me so

Me vi peso me 2-7 ТМеМУ ВЕУ ЭО о я

Me 2 Me Me 73 o Me Me

Me m, An, Me Me nn napchunlnamy fin sn Y nnnanvannnnnnnnia shchi ich

Me Me Me 30 Me with sch (8)

Example 13

Hydrochloride 2-methyl-1-(3,3,5,5-tetramethylcyclohexylidene)-2-propanamine (31) a) 2-methyl-1-(3,3,5,5-tetramethylcyclohexylidene)-2-propanol (29 )

A solution of acetate 2 (2.14 g, TOmmol) in diethyl ether (200 ml) was added to a 1.6 M solution of Mey and in diethyl CO ether (2 bml, 40 mmol) while cooling in an ice bath. The reaction mixture is stirred at room temperature for an hour. Then it is cooled in an ice bath and saturated aqueous MN Si (20 ml) is added dropwise. The aqueous phase is extracted with diethyl ether (2x3Oml). The combined organic phases are washed with a saturated salt solution (3 mL), dried over NaOH, filtered and evaporated. The residue is purified by distillation in the apparatus (U

Kideigoig with a short nozzle (1002C/4mm Hg), yielding 29 (1.86g, 8696) as a colorless oil. "N-NMR m

Zo (SOSIZ, TM5), m.p.: 0.91 and 0.96 (total 12H, both c, cyclohexane-3,5-CH3z), 1.25 (2H, c, cyclohexane-4-CH5); 1.38 (6H, s, - Ch(SNZ)20); 1.79 and 2.23 (both 2H, both c, cyclohexane-2,6-CH»o) and 5.39 (1H, c, -CH-).

B) 2-azido-2-methyl-1-(3,3,5,5-tetramethylcyclohexylidene)propane (30)

БезЗЕСО (0.3 ml, 2.4 mmol) is added to a solution of alcohol 29 (0.42 g, 2 mmol) and TM5M»z (0.31 ml, 2.4 mmol) in dibenzene (4.5 ml) during Zhv. when cooling in an ice bath. The reaction mixture is stirred at 5-102C for an hour. and filtered through a short silica gel column. The solution was evaporated and the residue was purified by flash chromatography on silica gel (light petroleum ether) to give ZO (0.30 g, 6495) as a colorless oil. TN-YAMe (SOCI3, TM5), m.p.: 0.92 and 0.98 (total 12H, both c, cyclohexane-3,5-CH»z); 1.27 (2H, c, cyclohexane-4-CH"); 1.40 (6Н, с, -С(СН3з)»М»а); 1.85 and 2.23 (both 2H, both c, cyclohexane-2,6-СНо) and 5.27 (IN, c, -СНУ-). -1 c) 2-methyl-1-(3,3,5,5-tetramethylcyclohexylidene)-2-propanamine hydrochloride (31)

Obtained from azide ZO by the same method as for amine 24 (example 4). The hydrochloride of amine 31 is obtained as a colorless solid with a yield of 6995. »z); 1.26 (2H, c, cyclohexane-4-CH»); 1.68 (6H, c, -C(SNUZ)»M); 1.84 and 2.10 (both -I 50 2H , both c, cyclohexane-2, 6-CH"); 5.15 (1H, c, "CH-) and 8.5 (ZH, shyr.s, MH").

Scheme: examples 14 and 15

IR e)

F) name) 60 b5

Scheme: examples 141 15 ; t in NuNs!

Mom 1 AN, BO ry now nvdiya and

Me ZNO, Me me 2NSyBO Me

Me Me SN, me me Me and 33 for kan 35 Ken 395 KeMe 40 peMe mam, and peme sleep, " o e sleep,

M 1, Memoi, BBO and

Me Me me Me de Me 36 C 18 s 29 Example 14 Ge)

3,5,5-trimethyl-2-cyclohexen-1-amine hydrochloride (35) a) 3-azido-1,5,5-trimethyl-1-cyclohexene (34)

To a cooled (02С) suspension of sodium azide (0.81g, 12.5mmol) in СНоСи» (ml) add dropwise 53905 aqueous

NBO, (in 8 ml). The mixture is stirred for 10 min., then a solution of 3,5,5-trimethyl-2-cyclohexanol (33) 30 μl (0.70 g, Bmmol) in СНоSiO (in Bml) is added. The mixture is stirred for 20 hours, poured into ice water, neutralized with aqueous MNAOH and extracted with СНоСиИ». The extract is washed with saturated salt solution and dried over Mo5O. "

Filtration and evaporation of the solvent while maintaining the temperature below 25 C give an oil, which is isolated by column chromatography on silica gel (light petroleum ether). The fraction with B 0.8 (hexane) is collected. M) 35 Evaporation of the solvent gives 34 as a colorless oil (0.365 g, 4496). "H-NMR (SOCI3, TM5), m.p.: 0.89 and i- 1.01 (total 6H, both c, 5,5-CH"); 1.34 (1H, m, cyclo-4 -CH); 1.55-1.95 (ЗН, m, 4-СН, 6-СН»); 1.71 (ЗН, с, 1-СН»); 3.90 (1Н, m, 3- CH) and 5.39 (1H, c, C-CH). 5) 3,5,5-trimethyl-2-cyclohexen-1-amine hydrochloride (35)

Obtained from azide 34 according to the procedure for compound 11 (example 3, c). Hydrochloride of amine 35 is obtained in the form of a colorless solid with a yield of 5795. TN-NMR (SOCI3, TM), m.p.: 0.89 and 1.03 (total bH, also c both c, 5.5-CH" with); 1.25-2.15 (4Н, m, 4,6-СН»); 1.72 (ZN, c, 3-CH3z); 3.88 (1IN, m, 1-CH); 541 (1IN, s, С-СН) and ц 8.40 (ЗН, шир.с, МНз"). "» Example 15

Hydrochloride of 1,3,5,5-tetramethyl-2-cyclohexen-1-amine (40) a) Mixture of 1,3,5,5-tetramethyl-1,3-cyclohexadiene (37) and 1,5,5-trimethyl -3-methylene-1-cyclohexene (38) -and To a 2M ether solution, which is being stirred, methylmagnesium iodide (15 ml, 0 mmol) is added dropwise a solution of 3,5,5-trimethyl-2-cyclohexen-1-one (36) ( 1.38g, 1Omol) in anhydrous ether (15ml). The mixture is stirred for 1 hour, cooled with ice water and carefully treated with 1595 aqueous CH with COOH (15 ml). Mixture

Cheka" stir for another hour. The organic layer is separated and washed with water and saturated aqueous Manso with. -1 50 After drying over Mo50O4, the solution is concentrated in a vacuum. The residue was purified by flash chromatography (light petroleum ether, CT 0.95 (hexane) to give a mixture of 37 and 38 (0.955g, 7095) (7:10, based on GC) as 42) as an oil. "H-NMR (SOS, TM5), m.p.: 0.89, 0.98 and 1.03 (total 10.2 H, all c, 5.5-SNU); 1.55-2.20 (only 12.6

H, m, СНЦС- and СНзо-); 4.69 (2H, dmb 4Hz, CH"); 5.06 (0.7Н, m, CH); 5.50 (0.7H, septet, 1.5Hz, CH) and 5.92 (IN, m, -CH).

B) 3-azido-1,5,5,5-tetramethyl-1-cyclohexene (39) o Obtained from a mixture of 37 and 38 according to the method for compound 34 (example 14, a). Azide 39 was obtained as a colorless oil with a yield of 4395. "H-NMR (SOCI3, TM), m.p.: 0.93 and 0.99 (total 6H, both c, 5.5-CHa); 1.31 (ZH; o c, 1-CH»U); 1.36 and 1.62 (total 2H, both d, 13Hz, 4-CH»); 1.72 (5H, c, 1-CH»z, 6 -CH"); 5.32 (1H, c, C-CH). c) 1,3,5,5-tetramethyl-2-cyclohexen-1-amine hydrochloride (40) is obtained from azide 39 according to the method for compound 11 (example 3, c).

The hydrochloride of amine 40 is obtained as a colorless solid with a yield of 6095. "H-NMR (SOCI",

TM5), m.p.: 0.96 and 1.07 (total 6Н, both с, 5,5-СН»з); 1.56 (ZN, c, 1-CH»U); 1.73 (ЗН, с, 3-СНа»); 1.60-2.05 (4Н, m, 4,8-СН»); 5.49 (1Н, с, С-СН) and 8.27 (ЗН, шир.с, МНз").

Scheme: example 16 b5

Scheme example 16 o y g aa su" va Yo

Me dz Me 70 of 43

With ia, 2 above

It's a visit to the city

Me " Me

Example 16

Hydrochloride of 1,3-trans-5-trimethyl-cis-3-vinylcyclohexanamine (45) a) 3,5-dimethyl-3-vinylcyclohexanone (42) 1M solution of vinylmagnesium bromide in THF (9Oml, UOmmol) is cooled in a bath of anhydrous ice-acetone to -209C in an inert atmosphere and add SisSiI (4.45g, 4Bmmol) in one portion. The mixture is stirred for 30 minutes. and c add dropwise a solution of 3,5-dimethyl-2-cyclohexen-1-one (41) (3.73 g, 0 mmol) in THF (40 ml), maintaining the reaction temperature at -202C. The cooling bath is removed and the temperature of the reaction mixture is allowed to rise to room temperature within 2 hours. Add fully saturated aqueous MN SI (5 Oml) while cooling in an ice bath. Then hexane (1500 ml) is added and the aqueous layer is separated and extracted with hexane (2 x 100 ml).

The combined organic extracts are washed with 2095 aqueous acetic acid (100 ml) and saturated aqueous MansSo»z so i y - (3x20Oml). The extract is dried over Ma5O), filtered and evaporated. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 20:11) to give 42 (2.4 g, 52965) as a colorless oil. TN-NMR (SOCI5, TM5), m.p.: 0.99 (ZH, d, bHz, 5-CH"); 1.11 (ZN, c, 3-SNU); 1.2-2.6 (7Н, m, ring protons); 4.94 and 5.01 (total 2H, both d, 17 and 10.5Hz, CH") and 5.64 (1H, dd, 17 and 11Hz, CH). t)

B) 1,3-trans-5-trimethyl-cis-3-vinylcyclohexanol (43) im-

A solution of ketone 42 (1g, b,bmmol) in diethyl ether (MOml) was added to a 1.6M solution of methyllithium in diethyl ether (12ml, 19,bmmol) while cooling in an ice bath. The resulting mixture is stirred for an hour. at 0-59C and add fully saturated aqueous MNAS! (1 Oml). The aqueous layer is separated and extracted with diethyl ether (2 x 15 ml). The combined organic phases are washed with a saturated salt solution (20 ml) and dried over Mo53O). The extract is filtered and evaporated. The crude product is purified by flash chromatography on silica gel (395 ethyl acetate in light petroleum ether). Cyclohexanol 43 (0.82 g, 74965) is obtained as a colorless oil, which is used in the next stage without characterization. "» c) 1-azido-1,3-trans-5-trimethyl-cis-3-vinylcyclohexane (44)

Obtained from cyclohexanol 43 according to the method for compound 9 (example 3, B). Azide 44 was obtained as a colorless oil with a yield of 1795. TN-NMR (SOSIS, TM5), m.p.: 0.94 (ZH, d, 6.5Hz, 5-CHz); 0.97 (ZN, c, -| 3-SNU); 1.27 (ЗН, с, 1-СН»); 0.7-2.0 (7Н, m, ring protons); 4.95 and 4.97 (total 2H, both d, 18 and 11Hz, CH") and sl 5.77 (1H, dd, 18 and 11HzC, -CH). a) Hydrochloride of 1,3-trans-5-trimethyl-cis-3-vinylcyclohexanamine (45) t» Obtained from azide 44 according to the procedure for compound 11 (example 3, c). The hydrochloride of amine 45 is obtained in the form of -I 20 as a colorless solid with a yield of 32965. TN-NMR (SOSIZ, TM5), m.p.: 0.92 (ЗН, d, 6.5Hz, 5-СН»); 0.96 (ZN, c, 3-CH»U); 1.45 (ZN, c, 1-CH»z); 0.8-2.1 (9Н, m, 2,4,6-СН», 5-СН and Н20б); 4.94 and 4.97 (2H, both d, 18 and so 11Hz, CH"); 5.76 (1H, dd, 18 and 11 Hz, CH) and 8.26 (ZH, shir.s, MHz").

Scheme: example 17

F) name) 60 b5

Scheme: example 17 and see

SHY memai Me OM 0 Alil in;

Me SOS! -/-snnnnnnyamiv. I

Sesi Me Man, dmso

Ma: COOEI 70 catalyst Ma 46 4

Me Me s o 8 i; and d- 1. dus "NS

Me price Me J

Me sov 2. MAYUN, Me with 3. on 49

Example 17

Hydrochloride 2-(1,3,3,5,5-pentamethylcyclohexyl)-4-pentenylamine (49) a) Ethyl 2-cyano-2-(1,3,3,5,5-pentamethylcyclohexyl)acetate (47)

Copper(1) chloride (0.05g, 0.5mmol) was added to cooled (-102C) 1M methylmagnesium iodide in ethyl ether (15ml, 15mmol) in an argon atmosphere and stirred for 5 minutes. Then a solution of acetate 46 (o) (2.5 g, TOmmol) in THF (25 ml) is added dropwise over 20 min., maintaining the temperature below 02C. The mixture is stirred for 1 hour, quenched with saturated aqueous MHCl and extracted with diethyl ether. The extract is washed with saturated salt solution, dried over anhydrous MoazO), filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 20:1) to give 47 (1.5 g, 56.590) as a colorless oil. TN-YAMe (SOSIZ, TM5), m.p.: 1.01, 1.07 and 1.09 (total 12Н, с, 3,5-СН»); 1.00-1.85 (6Н, m, и - CH ring); 1.30 (ЗН, с, 1-СН»); 1.33 (ZH, t, 7Hz, CH3-ethyl); 3.44 (1H, s, 2-CH) and 4.27 (2H, kv, 7Hz, OSN"). "Mr

B) Ethyl 2-cyano-2-(1,3,3,5,5-pentamethylcyclohexyl)-4-pentenoate (48)

Sodium hydride (0.284 g, o

Z5 7.b09 mmol; 6075 dispersion in mineral oil). The mixture is stirred for ЗОхв. at 509C and cooled to M 2020. Allyl bromide (0.86g, 7.mmol) is added to this mixture and the mixture is stirred for hours. at room temperature, then ЗОхв. at 502C. The mixture is cooled, treated with water and extracted with diethyl ether.

The extract is washed with water and saturated salt solution, dried over anhydrous MozO), filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 20:1) to give 48 (0.92g, 63.795) as a colorless oil. "H-NMR (SOCIx, TM8), m.p.: sh s 0.98 (6H, s, 35-CHzed); 1.11 (6H, s, 35-CHzach); 1.00-1.85 (BN, m, CH ring); 1.31 (ZN, t, 7Hz, CH3-ethyl); 1.33 "z (ZN, c, 1-CH"); 2.42 and 2.86 (total 2H, both dd, 13 and 7Hz, 3-CH"); 4.02 (2H, square, 7Hz, OSN"); 5.05-5.37 (2H, m, "CH") and 5.55-6.05 (1H, m, CH). c) Hydrochloride 2-(1,3,3,5,5-pentamethylcyclohexyl) -4-pentenylamine (49)

Water (0.53 mL, 2.95 mmol) and lithium chloride (0.25 g, 5.9 mmol) were added to a solution of ester 48 (0.9 g, 2.95 mmol) in DMSO (1 mL). The mixture is stirred during the Agreement. at 175-1802С, then cool and add water with (ZOml). The mixture is extracted with diethyl ether. The extract is washed with water and saturated salt solution, dried over anhydrous Ma95O5, filter and concentrate to a volume of 10 ml. The resulting solution is added dropwise to a suspension of lithium aluminum hydride (0.25 g, b, bmol) in diethyl ether (1 bml) and boiled with a reflux condenser for 20 hours. The mixture is cooled, treated with 2095 aqueous Mahon and extracted with diethyl ether. The extract is washed with a saturated salt solution, dried over Mahon, filtered and treated with an anhydrous solution of HCIII in diethyl ether. After evaporation of the solvent, the residue was purified by silica gel chromatography (chloroform-methanol, 20:1) to give 49 (0.245g, 3195) as a colorless solid. 1H-NMR (DMSO-Ov, TM5), m.p.: 0.92, 0.96 and 1.04 (total 15H, all s, 3,5-CH2 and 1-CH»z), 1.00 -1.65 (total B6H, m, ring-CH»e»); 1.85-2.40 (ЗН, m, 3-СН», 4-СН); 2.60-3.10 (2Н, m, СНМ); 4.90-5.25 (2H, m, CH);

HF) 5.62-6.10 (1Н, m, СН) and 7.92 (ЗН, шир.с, МНз 7). with PHARMACEUTICAL COMPOSITIONS

The active ingredients of the present invention, together with one or more conventional adjuvants, carriers or diluents, can be prepared as pharmaceutical compositions and unit dosage forms thereof, and in such form can be administered as solid compositions such as coated or uncoated tablets or filled capsules or liquids such as solutions, suspensions, emulsions, elixirs or capsules filled therewith, all for oral use; in the form of suppositories or capsules for rectal use or in the form of sterile solutions for injections for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may contain known or novel ingredients in conventional or special proportions, with or without additional active compounds, and such unit dosage forms may contain any suitable effective amount of active ingredient appropriate to the intended range of administration. daily doses Thus, suitable typical unit dosage forms are tablets containing from twenty (20) to one hundred (100) milligrams of the active ingredient, or, more broadly, from ten (10) to two hundred and fifty (250) milligrams per tablet.

METHOD OF TREATMENT

Due to the high degree of their activity and low toxicity, which together represent the most favorable therapeutic indicator, the active substances of this invention can be administered to a subject, for example, into the body of an animal in need (including a person) for treatment, relief or reduction of intensity, 7/0 temporary alleviation or elimination of an indication or condition susceptible thereto, or a typical indication or condition specified elsewhere in this application, preferably competitively, simultaneously or together with one or more pharmaceutically acceptable excipients, carriers or diluents, especially and preferably in the form of their pharmaceutical compositions orally, rectally or parenterally (including intravenous and subcutaneous methods), or in some cases even locally at an effective amount. Suitable dosage ranges are 1-4000 mg per day, preferably 10-500 mg per day, and especially 50-500 mg per day depending, as a rule, on the exact route of administration, form of administration, indication for which the administration is directed, sub the participating subject, the participating subject's body weight, and the preference and experience of the attending physician or veterinarian.

EXAMPLES OF TYPICAL PHARMACEUTICAL COMPOSITIONS

With the help of commonly used solvents, auxiliary agents and carriers, the products of reactions 2o can be processed into tablets, coated tablets, capsules, dropper solutions, suppositories, preparations for injections and infusions and the like, and can be used therapeutically by oral, rectal, parenterally and other ways. Typical pharmaceutical compositions are given below. (a) Tablets suitable for oral administration containing the active ingredient may be prepared by conventional tableting techniques. (B) For suppositories, any conventional suppository base may be used to incorporate the active ingredient by a conventional method, such as polyethylene glycol, which is solid at normal room temperature but melts at or near body temperature. (c) For solutions for parenteral (including intravenous and subcutaneous) administration, the active ingredient is used together with the usual ingredients in the usual amounts, such as, for example, sodium chloride and double-distilled water, as needed, according to a usual technique, such as filtration , aseptic filling of ampoules or bottles for intravenous drips, and processing in an autoclave for - sterility. "Mr

Other suitable pharmaceutical compositions will be readily apparent to those skilled in the art.

The following examples are also given for illustration only and are not limiting. at

EXAMPLE 18-

Drug for tablets

A suitable preparation for a tablet containing 1Omg of the active ingredient is the following:

MG "

Active ingredient 10 -o

Lactose 63 with Microcrystalline cellulose 21 with Talc 4

Magnesium stearate 1

Colloidal silicon dioxide 1

B. EXAMPLE 19 1 Tablet formulation Another suitable tablet formulation containing 10mg of active ingredient is as follows: -0.720 meso Active ingredient 100

Potato starch 20

Polyvinylpyrrolidone 10

Covered with a film and colored

GF) The material of the covering film consists of: Lactose 100

Microcrystalline cellulose 80 bo Gelatin 10

Cross-linked polyvinylpyrrolidone 10

Talc 10

Magnesium stearate 2

Colloidal silicon dioxide Z bo Color pigments B

EXAMPLE 20

Drug for capsules

A suitable preparation for a capsule containing 5Omg of the active ingredient is the following:

MG

Active ingredient BO

Corn starch 20

Dibasic calcium phosphate 50 70 Talc 2

Colloidal silicon dioxide 2

Fill the gelatin capsule.

EXAMPLE 21

Solution for injection A suitable formulation for a solution for injection containing one percent of the active ingredient is as follows:

Active ingredient, mg 12

Sodium chloride, mg 8

Sterile water up to ml

EXAMPLE 22

Liquid preparation for oral administration

The appropriate drug for 1 liter of liquid mixture containing 2 mg of the active ingredient in one ml of the mixture is the following: o g

Active ingredient 2

Sucrose 250 (2.0)

Glucose ie/0)8) che

Sorbitol 150

Orange flavoring 10 "

Dye Zipvei uePyom yu

Purified water up to a total volume of 1000 ml

EXAMPLE 23

Liquid preparation for oral administration

Another suitable preparation for 1 liter of liquid mixture, containing 20 mg of the active ingredient in one ml of the mixture, is the following: - c g i » Active ingredient 20.00 p Tragacanth 7.00

Glycerin 50.00

Sucrose 400.00 - I Methylparaben 0.5BO0 s Propylparaben 0.05

Blackcurrant flavoring 10.00 Soluble red dye 0.02 -I 50 Purified water to a total volume of 1000 ml so EXAMPLE 24

Liquid preparation for oral administration

Another suitable preparation for 1 liter of liquid mixture containing 2 mg of active ingredient in one ml of mixture is the following:

F, A ke Active ingredient 2

Sucrose 400 in. Infusion of bitter orange peel 20

Infusion of sweet orange peel 15

Purified water up to a total volume of 1000 ml

EXAMPLE 25 65 Aerosol preparation 180 g of aerosol solution contains:

Mr

Active ingredient 10

Oleic acid B

Ethanol 81

Purified water 9

Tetrafluoroethane 15

Aluminum cans for agrosol are filled with 15 ml of this solution, closed with a dosing valve, /o0 creates a pressure of 3,000 bar.

EXAMPLE 26 tOr5-preparation 100 g of solution contain: g i. and

Active ingredient 10.0

Ethanol 57.5

Propylene glycol 7.5

Dimethylsulfoxide Bo

Hydroxyethyl cellulose 0.4

Purified water 19.6 1.8 ml of this solution is placed on a cloth covered with a sticky foil backing. The system is closed with a protective gasket, which is removed before use.

EXAMPLE 27 cm

The drug in the form of nanoparticles 10 g of polybutylcyanoacrylate nanoparticles contain: o g

Active ingredient 1.00

Poloxamer 010 so

Butyl cyanoacrylate 8.75 u

Manit 010

Sodium chloride 0.05 M

Io)

Polybutylcyanoacrylate nanoparticles are obtained by emulsion polymerization in a water/0.Tn mixture. HCl/ethanol as 32 polymerization medium. Finally, nanoparticles in suspension are lyophilized in a vacuum. -

PHARMACOLOGY - BRIEF DESCRIPTION

The active substances of this invention, their pharmaceutical compositions and methods of treatment with their help are distinguished by unique advantages and non-obvious properties, making the declared "material, considered in general" in this description, non-obvious. These compounds and their pharmaceutical compositions demonstrate the following properties and non-assessable characteristics in standard, generally accepted research methods that deserve trust: c» They are systemically active, non-competitive antagonists of MMOA receptors with fast blocking/unblocking kinetics and strong stress dependence and, therefore, are useful in treating, terminating, ameliorating, attenuating, or reducing the intensity of susceptible conditions by administration or administration to a carrier animal for the treatment of a wide range of CNS disorders that include disorders of glutamatergic β-transmission. These compounds are also systemically active, non-competitive antagonists of 5-HT3 receptors and neuronal nicotinic receptors and, therefore, are useful in the treatment, termination, relief, attenuation or reduction in intensity of susceptible states by application or administration to a carrier animal for the treatment of a wide range of -I 20 range of CNS disorders that include disorders of serotonergic or nicotinic transmission.

Research methods of receptor binding

Male Zrgadce-Oamiem rats/ (200-250g) are decapitated and brains are quickly removed. The bark is excised and homogenized in 20 volumes of ice-cooled 0.32M sucrose using a glass-Teflon 22 homogenizer. The homogenate is centrifuged at 1000 x 9 for 10 minutes. The precipitate and the supernatant are discarded

F! centrifuge at 20,000x49 for 20 minutes. The resulting sediment is resuspended in 20 volumes of distilled water and centrifuged for 20 minutes. at 8000x Then the supernatant and the leukocyte film are centrifuged at 48,000 x 9 for 2 hours. in the presence of BOMM Tris-HCl, pHaZ, 0. Then the sediment is resuspended and centrifuged two or three times at 48,000 rpm for 20 minutes. in the presence of 50 mM Tris-NSII, pH NaV, 0. All stages of centrifugation 60 are carried out at 42C. After re-suspension in 5 volumes of 5X0 mM Tris-HCl, pH8.0, the membrane suspension is quickly frozen at -8026.

On the day of the study, the membranes are thawed and washed four times with resuspension in 50 mM Tris-HCl, pH 0, and centrifugation at 48,000 x 9 for 20 minutes. and finally re-suspend in 50MM

Tris-NSII, pH7.4. Determine the amount of protein in the final membrane preparation (250-50 Ωkg/ml) according to the b5 method of Lowry et al. (1951). Incubation begins with the addition of (NI-(7k)-MK-801 (23.9 curie/mmol, 5nM, Yuiropi

MEM) into test tubes with glycine (10mμM), glutamate (1μM) and 125-250μg of protein (total volume 0.5ml) and different concentrations of the agents under investigation (10 concentrations, each duplicated). Incubation is carried out at room temperature for 120 minutes. (reach equilibrium under the conditions used). Nonspecific binding is determined by adding unlabeled ()-MK-801 (10μM). Incubation is completed using the MiSchroghe filter system. The samples are rinsed twice with 4 ml of ice-cooled research buffer on glass fiber filters (ZspIesneg y: Zspceii) under constant vacuum. After separation and rinsing, the filters are placed in a scintillation liquid (bml, OMKita (zoYi4) and the radioactivity retained on the filters is determined with the help of a conventional liquid scintillation counter (Nemei Raskaga, Hidtsii ZsipiPayop 70 Apaiuzeg). Ka IZNI-(n-MK-801 for 4.6nM is determined by the Scratchard assay and used according to the Chen-Prussov ratio to calculate the affinity of the substituents as Ka values. Most antagonists are tested in 3-7 separate experiments.

Expression of the MMOA receptor subtype and neuronal nicotinic receptors in Heporiz oocytes

Mature female individuals of Heporiz Iaemiz are anesthetized in 0.295 tricaine on ice for 15 minutes. up to 75 operative interventions. Oocytes are removed and incubated in 2 mg/ml collagenase (type II) in oocyte solution

Ringer's, which does not contain Ca?! (82.5mM, Masi, 2mM KS, 2mM Masi», 5mM NEREZB, pH7.5), during ЗОхв. at room temperature and thoroughly washed with OK-2 (100 mM Masi, 2 mM KS, 1 mM Masi», 2 mM Sasi», BMmM NEREB5, pH7.5). The remaining layer of follicular cells is manually removed with pointed tweezers and the oocytes are stored in OBC-2. RNA is dissolved in OERS-treated sterile distilled water. RNA for the MMOA subunit MKia is mixed in a ratio of 1:11 with RNA for the MMOA subunit MAK2A. Similarly, neuronal nicotinic A4 RNA is mixed in a 1:1 ratio with RNA for the B2 subunit. Fifty to one hundred nanoliters of each RNA mixture is injected into the oocyte cytoplasm using a nanoliter injector (UUopa

Rgesiviop of Ipsigitepi). Oocytes are incubated at 192 in OK-2 for the next 3-6 days.

Electrophysiological responses are obtained using the standard two-electrode method of voltage-blocking C (amplifier SepesSiatr 500) within 2-6 days after the injection. The electrodes have a resistance between about 0.2 and 04MoΩMm and are filled with ZM KSiY. Registration is made in a custom-made chamber with 2-3 second exchange times. The solution for the bath is prepared without Ca 2", avoiding Ca"-induced SI'-currents (100 mM mass, 2 mM KS, 5 mM NEREZ5, 2 mM Vasi", pH7.35). MMOA receptors are manually activated by applying together 1mM glutamate and 10μM glycine for 30-4 seconds. every 2-3 minutes in oocytes blocked at -7ΩmV. Neuronal so nicotinic receptors are activated by applying 100 µM acetylcholine for 20-300 seconds. every 2-3 minutes on oocytes blocked at -7O0mV. After obtaining stable control responses, complete concentration-response curves with antagonists are obtained by preliminary incubation of 6-7 different concentrations with intervals of 3.

Only results from stable cells are acceptable for inclusion in the final study, namely those showing at least 5095 recovery of responses to MMOA after removal of the test antagonist.

Despite this, recovery from the effect of drugs is not always 10095 due to slight attenuation or acceleration in c. some cells. This effect, if present, is always compensated for by putting in an initial 95% antagonism at each concentration for control and recovery and allowing a linear time course for this attenuation. All antagonists are evaluated in a stable state of blockade at 6-7 concentrations, at least on 4" cells. Equilibrium blockade is achieved within the limits of the use of 1-3 agonists, depending on the concentration of antagonists. c) c Kinetic experiments are carried out using different concentrations of unsaturated aminoalkylcyclohexanes "" (usually 5 concentrations according to the dosage scheme court 3) for 10-20 seconds in the constant presence of glutamate " (10 ОмМкМ) and glycine (1 ОМКМ) for 90-18О0 seconds. in Heporiz oocytes expressing MKa/2A receptors.

The perfusion system used for these experiments is a modified oocyte carousel system that allows rapid infusion and washout of agonist and antagonist with replacement periods of less than one second. Exponential dependencies are obtained using the TISOA program for MUipdomuz, and most of the responses are well described by a simple exponential dependence. The same system is used to obtain the dependence of blockade on voltage, but the solution in the bath contains flufenamic acid (100 µM) to block endogenous voltage-activated and Ca?-activated SI currents. Also, Ba? (2mMM) are replaced by low - I 50 concentrations of Ca 27 (0.2mMM). After equilibrium blockade at high concentrations of the antagonist (usually with 10-fold values of ISvo), I get five slopes from -7ΩmV to "ZOmvV" in two seconds. Similar slopes are obtained for solutions in the bath and for glutamate without an antagonist, before the application of the antagonist and after the restoration of responses. Leaks in the absence of glutamate are subtracted from the curves for glutamate and glutamate plus antagonist.

The voltage dependence is then determined by comparing the curves for glutamate and glutamate plus antagonist. 59 Blocking of receptors for MMA and nicotine

HF) Hippocampi are obtained from rat embryos (E2O and E21) and transferred to a salt solution with Hank's buffer, which does not contain calcium and magnesium (Sibso) on ice. Cells are mechanically dissociated in a mixture of 0.0590 DNase/0.390 ovomucoid (Zidta) after an 8-minute pre-incubation with a mixture of 0.6695 trypsin/0.195 DNase (Zidta). Then the separated cells are centrifuged at 18x9 for 1 hour, re-suspended in a minimal support medium (bibso) and seeded at a density of 150,000 cells cm? in plastic Petri dishes (RaiYsop) pre-coated with poly-I-lysine (Zidta). Cells are provided with a minimal maintenance medium with ManNsSOzZ/NEREB buffer with the addition of 595 fetal calf serum and 590 horse serum (sirso) and incubated at 372C, 5956 СО» and 9595 humidity. The medium is completely changed after inhibition of ongoing glial mitosis with cytosine-O-arabinofuranoside (20M Zidt) approximately 7 days ip myo. After that, the medium is partially replaced twice a week.

Registration of blocking receptors is carried out from these neurons using polished glass electrodes (4-6MOm) according to the method of the whole cell model at room temperature (20-22) using an EPC-7 amplifier (II). The substances under investigation are applied by switching the channels made on

Ordering a fast superfusion system with normal output (exchange time 10-20 ms). The components of the intracellular solution are as follows (mM): SuSi (120), TEASI (20), ESTA (10), Mosi" (1), SaSiI (0.2), glucose (10), ATP (2), TsAMP (0 ,25); The pH is adjusted to 7.3 with C8zOH or HCI. Extracellular solutions have the following main composition (mM): Mass (140), KSI (3), SasSi" (0.2), glucose (10), NEREB5 (10), sucrose (4.5), tetrodotoxin (ТХ 32107) , All solutions contain glycine (1M) at a concentration sufficient to cause 70 approximately 80-8595 activation of glycine receptors. Only results from stable cells are acceptable for inclusion in the final study, namely, corresponding to the recovery of responses to MMOA, with their at least 7595 depression by the antagonists under study.

Blocking receptors for 5-HT3

MTE-115 cells are purchased from the European Cell Culture Collection (ESASS, Zaivrigu, OK) and stored at -80°C until further use. Cells are sown at a density of 10,000 cells-cm 2 in plastic cups

Petri dishes (Raisop) and provide minimal support medium (MEM) with ManNsSozZ/NEREZ buffer with the addition of 1595 fetal calf serum (birso) and incubate at 372С, 595 СО» and 9595 humidity. The environment is completely changed every day. Once every three days, cells are transplanted into fresh Petri dishes after treatment with a trypsin-EDTA mixture (195 in PB5), resuspension in MEM and centrifugation at 1000 rpm. within four minutes.

Recording of receptor blocking at -7ΩmV from the collected cells, 2-3 days after seeding, using polished glass electrodes (2-6MOm) using the whole-cell method at room temperature (20-222С) using an EPC-7 amplifier (II from ). The components of the intracellular solution are as follows (mM):

С8СИ (130), STAINLESS STEEL (10), ESTA (10), MosSi" (2), Sasi" (2), K-ATP (2), Tris-GTP (0.2), O-glucose (10); pH CM is brought up to 7.3 with the help of SzOH or NS. Extracellular solutions have the following basic composition (mM): mass o (124), KSI (2.8), NEREZ5 (10), рН7, З are adjusted with the help of Maon or NOSI.

After establishing the whole-cell configuration, the cells are harvested from the glass substrate and serotonin (1 ΩμM), memantine, and unsaturated aminoalkylcyclohexane derivatives are added at various concentrations using a rapid superfusion device. To influence the collected cells with a solution that does not contain or contains serotonin, a double-cylinder pipette controlled by a piezo transducer is used. A two-second burst of serotonin is delivered every bOsec. The intended antagonists are dissolved in doubly distilled water and diluted with a solution from the bath to the required concentration. Only results from stable cells are eligible for inclusion in the final study, namely those that demonstrate at least 5095 recovery of serotonin responses after removal of the compounds. Despite this, the recovery from other drugs is not always 100905 due to the attenuation of 3o in some cells ("1095 in 10 minutes"). This effect, if present, is always compensated for by setting a baseline of 95 antagonism at each concentration for control and recovery and allowing a linear time course for this attenuation. All antagonists are evaluated in a stable state of blockade at 3-6 concentrations, at least on five cells. Equilibrium blockade is achieved within the framework of the use of 2-5 agonists, depending on the concentration of the antagonist.

Ip mimo Z c Anticonvulsant effect "» For studies of maximum electric shock (ME5) and motor insufficiency, female mice "MMK (18-28g), placed 5 per cage, are used. All animals are kept without restriction of water and food with a 12-hour light-dark cycle (light after the morning) and regulated temperature (20 -0.52С). All experiments are carried out between 10 hours. morning and Sunday p.m. Agents under investigation are administered intraperitoneally according to ZOkhv. to induction it. convulsions, unless otherwise indicated (see below). All compounds are dissolved in 0.995 physiological saline. "sl ME5-test is carried out together with studies of myorelaxant effect (extension reflex) and motor coordination (rotating rod). To study the stretch reflex, mice are placed together with their front paws on a t-horizontal rod and required to fit all 4 paws on the wire in 1 second. To study ataxia (motor-I 20 coordination), mice are placed on a rotating rod, which accelerates, and required to remain on the rod for min. Only mice failing criteria in all three replicates of each study were considered to have demonstrated myorelaxation or ataxia, respectively. After these studies, ME5 is performed (100 HuC, shock duration 0.5 sec., shock intensity 5 OhmA, pulse duration 0.Omsec., Odo Vavia), carried out with the help of corneal electrodes. Note the presence of tonic convulsions (tonic extension of 22 hind legs with a minimum angle relative to the body of 902). The goal is to obtain ED 5o for all parameters

HF) (anticonvulsant action and motor side effects) noted when applying the Litchfield-Wilcoxon test for quantitative values of dose responses. The result of dividing ED 50 for side effects (ataxia or o myorelaxation) by ED o for antagonism of electroshock convulsions is used as a therapeutic index (v. 60 Statistical analysis

ICs in receptor blocking and binding studies are calculated according to the four-parameter logistic equation using the Ogai computer program (Epiasis Zoimage, Epodiapa). Then the Ki values for Chen-Prusov binding studies are determined. The binding values presented are the average values of 4 root mean square deviations from 3-5 determinations (each performed twice). for In each of the ip mimo tests, 4-7 doses of antagonists are studied (5-8 animals per dose), allowing the calculation

Estimated trees according to direct analysis (I ysiiYaeiy and MMisohop) with correction for 0-10095 effects. ED 5o are presented with a 9595 confidence interval (CI). To compare the effectiveness of ip migo and ip mimo anticonvulsant action, Pearson correlation analysis is used (Reagzop rgodisi totepi sogteiaiop apaiuziv) (Zidta 8ai,

Wow! Zsiepiyis).

RESULTS

Me2 numbers

MEl2 numbers are used to represent chemical names. MCA-numbers and corresponding chemical names are presented in the "MCA list". 70 List of MKs of the state and the

Connecting MK-80

All compounds are substituted by (NI-(7)-MK-801 with Ki values from 1 to 83 µM (see Table 1). ch i, 2

Aries 00 for 00000053. fell tilenuvenlie 0007600000000049000008001

Ро (тн 000000111мв011100000ю00111060зж00100000000ю in ziso ethyleneveninshche 00035343 "For the poet 00001002м501000100000890000060 03310056 000 (vtylenovne 0009000000000006о

Fio0000200o Nerameyuansultat 1680000000000000000000300000000 obro vtylenoveklie | 5l0100000blv1151

FD tu 0000010в3600100000000020000000530966010000000 580006 - 177 lob61111111ому 31111111 ram 00187 11111о51111108, 21000000»

Aries 00000100 28a0010000000b88000100053 vyat 1001010000vyat6

WHERE ARE WE NIM t: THEY ARE NOT MON POL A m ven 111010 3y201110о61111110800111 0016 vyv vmeno 111010 v3410110зюе61118,11

О0000оивтен000101010002»010000000з6611108 пл 10011100456000006 юри 0001010 69010001110о81000000033д801000000000и66 ув мно 000106 1012юб1108, ме 10000336 ле тен 1110100 130601000000 86111080 0 юємено 0111001 м510000000660330 ом тен 111010 в600100000000900110008 а 10000056 ото тиленювенинще 0468 01000000039100000800010 рвав лен 111111111111111111111111евв 111111 бо Результати для типових сполук наведені на Фіг.1.

EXPRESSION OF MMOA RECEPTOR SUBTYPE IN HAEMORA 5 OOCYTES

Blockade of MMOA receptors with the help of MKA 2/759 is determined by applying different concentrations (from 0.1 to 100μM in the dosing scheme of Isd 3) for 10 seconds, in the constant presence of glutamate (100μM) and glycine (1μM), at -7ΩmV for 100 seconds in Heporiz oocytes expressing MK1a/2A receptors (Fig. 2, left).

The effectiveness of MK 2/759 (ISvo-1.99μM, Niii 0.75) is determined by plotting the percentage of blockade against the concentration of the antagonist and then optimizing the curve according to the logistic equation (Fig. 2, right).

Plaque fixation

Responses of internal currents of freshly disconnected hippocampal neurons in steady state on MMOA (200M with glycine 7/0./7M at -70mV) are subjected to the antagonistic influence of MKA 2/759. Peaks and currents in the steady state are affected to the same extent, which makes it unlikely that their effects are mediated by the glycine site. Strong support for the non-competitive nature of this antagonism is provided by the clear dependence of its blockade on application and tension.

See Fig. 3.

YIP by

Anticonvulsant action

The results of MEZ and myorelaxation effect are presented in Table 2. 090010 evil was sown in the flesh 0000 lo9ovo 002z0yu 1523Bo) 006008 sch

EE NENNYA MON THEY MON POLON MON POL NANNYA o obli tu? zayalozya 446? 0000 two 0 catch left 08007 byu so z VENY WE BELT MON NOYA ON by t by oyu 10011818 - th battle 00000160 zv ENN NI NI NN MON MON NOY PO TUN M tt zvvvos91367, zve 00300223 0 hall? mandatory) 01000008

ANN THI NIM NI NI PO PON ZNNNO NOYA PNIA " z Z s byu 00010010 iz"

In conclusion, it is clear from the foregoing that the present invention relates to new, useful and unexpected applications and uses of the compounds of the present invention, which according to the present invention contain an active agent, as well as to their new pharmaceutical compositions and methods of their preparation and treatment using them, all they still have the characteristics and advantages listed in more detail above.

As is evident from the above text, the high degree of activity of the active agent of this invention and its compositions is an indicator of applicability for humans, as well as lower animals based on its beneficial activity. - 50 However, clinical evaluation in humans has not been completed. It will of course be understood that the distribution or sale of any compound or composition falling within the scope of this invention for human use will normally be based on the prior approval of governmental authorities such as O.5. Redega! Rosd apa Ogoid Aatipizigayop, who are responsible for this and are authorized to make decisions on such issues.

Conclusions 22 These unsaturated 1-aminoalkylcyclohexanes represent a new class of systemically active non-competitive

Gee! antagonists of MMOA receptors with fast blocking/unblocking kinetics and a strong dependence on tension. In view of their modest efficacy and associated rapid kinetics, they would be useful as therapeutic agents in a wide range of CNS disorders, including disorders of glutamatergic transmission. 60 Thus, these compounds are used in the treatment of the following disorders of the animal body, especially humans. 1. Excitotoxicity, such as stroke ischemia, trauma, hypoxia, hypoglycemia, glaucoma, and hepatic encephalopathy. 2. Chronic neurodegenerative diseases, such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis,

AIDS neurodegeneration, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron disease, 65 mitochondrial dysfunction, Korsakoff's syndrome, and Creutefeldt-Jakob disease. 3. Other disorders related to long-term plastic changes in the central nervous system, selected from chronic pain, drug tolerance, dependence and addiction (for example, opioid, cocaine, benzodiazepine, nicotine and alcohol). 4. Epilepsy, tardive dyskinesia, schizophrenia, anxiety, depression, acute pain, elasticity and tinnitus.

In addition, it was found that these compounds are also antagonists of neuronal nicotinic receptors and 5-HT receptors. Thus, the compounds of this invention are used in the treatment of disorders in the body of an animal, especially a human, with nicotinic and 5-HT3 receptor-mediated indications for symptomatic and neuroprotective purposes (for example, for the treatment of vomiting, nicotine abuse, schizophrenia, cerebellar tremor, mucous colitis, migraine, depressive disorders, cognitive disorders, psychosis, 7/0 associated with the treatment of Parkinson's disease, and appetite disorders).

In addition, as already established, due to its amine substituent, at least in part, the compounds of this invention are also effective in indications unrelated to the above-mentioned mechanism of action, demonstrating immunomodulatory activity, antimalarial and antitrypanosomal activity, activity against the virus

Vogpa, against the herpes virus and against the hepatitis C virus.

A method of treating an animal with a compound of this invention for the purpose of inhibiting the development of or ameliorating a selected ailment therein is, as previously established, any conventionally acceptable pharmaceutical method employing a selected dosage that is effective in ameliorating the particular ailment to be ameliorated.

The use of the compounds of this invention in the manufacture of a medicinal product for the treatment of an animal for the purpose of inhibiting the development of or ameliorating a selected disorder or condition, in particular, a disorder or condition amenable to treatment with an MMA receptor antagonist, a neuronal nicotinic receptor antagonist, a 5-HT3 antagonist, or a compound exhibiting immunomodulatory activity, antimalarial and antitrypanosomal effectiveness, activity against the Vogpa virus, against the herpes virus and against the hepatitis virus

C, is carried out in a conventional way, which includes the stage of mixing an effective amount of the compound of this invention with a pharmaceutically acceptable diluent, filler or carrier, and the method of treatment, pharmaceutical compositions and application of the compound of this invention in the production of a medicinal product. and)

Typical pharmaceutical compositions prepared by mixing the active ingredient with a suitable pharmaceutically acceptable excipient, diluent, or carrier include tablets, capsules, injectable solutions, oral liquid preparations, aerosol preparations, TOZ preparations, and so-called nanoparticulate preparations, providing , thus, medicinal preparations for oral administration, administration by injection or dermal application according to the above. -

It is to be understood that the present invention is not limited to the precise details of the operations shown and described or to the precise compositions, methods, techniques, or variants as obvious modifications and equivalents will be apparent to one of ordinary skill in the art, and therefore the present invention is limited only to all areas that may be legally bring Shcheo, zv In accordance with the attached claim. uh-

References 1. K.S. Ehapk, N.K. Naked! (1950) 3. At. Spent boss. 72:1645-1648. 2. S.A. Niedei, R. Vygk. (1973) U. Ogd. Spent 38:3637-3639.

Z. M.R. Riitei, R.MU. Nobody (1970) 93. Spet. wasps P:716-719. " 4. O.N. Razpeg, I.H. Egue. (1984) Ivg. U. Spet. 24:88-92. from p. 5. O.I. I etiege, T.D. map Ozzeiaeeg, E.S. Apdegmeigeiai. (1978) ViiYi. wasps Sleep Veid. 87:771-782.

And 6. V.O. Noize, U.M. UMiKipv. (1976) 9. Oh. Spent 41:(25) 4031-4033. and?" 7. A.K. Ogeepamau, M.V. MUpaiIeu. (1976) U. Speth. wasps R.T. 1.: 1385-1389. 8. 5. Maivigama, U. Nogidispi, E. MaKatiga, I. Kimaita. (1989) Teigapedop 45:(2) 349-362. 9. V.O. Noize, M.R. Rizspeg. (1968) 93. Ogd. Spent 33:(3) 949-956. -I 10. Spisgaodism, b., Madiesiyaits, A. (1954) ViiYi. wasps Sleep Veid. 63: 357-378. 11. 2aidiem/isg, M, Ogagem/is:2 A., 2aspagemisg, MU. (1964) Kosgpiki Speth. 38: 591-597. at 12. Stovzvivu, AMU., Spo, S (1910) 9. Spet. wasps 2218. their 13. 2aidiem/isg, M., Ogagemisg, A. (1971) Kospiki Spet. 45: 1187-1194. 14. | also, ET, map deg Maav, .N. (1981) Zresigospita. Asia, A. Z8A: 283. - 15. | also, ET, map deg Maav, .N. (1981) Zresigospita. Asia, A. 37A: 129-134. p. 16. Kataipdat K., Vaiasibgatapiap, M., Vaiyan, M. (1972) Ipaiap U. Spet. 10: 366-369. 17. Natiip, K.E, EgeigeiIdeg, M. (1953) 9. At. Spent boss. 75: 369-373. 18. Nazzpeg, A., Riripdeg, K., Apaivik, O.Yu. (1984) 93. Ogud. Spent 49: 4237-4244. 19. MU. Oapuvzl, S.O. Ragzopv, I. Vgevipk, b. Otschask (1995) Abomination Memuz Regzresi. 8:261-277. 20. U.O. And eapaeg, K.K. And amugop, R.I.., Ogpavivip, O.M. Attegtap (1988) Vgaip Kez. 448:115-120. (F) 21. S... Ragvopv, S. OtsasK, I. VgevipK, YII. Vagap, E. RggedaiijpeKi, MU. KoviomuvKi, R. Kglavsik, 5. ka Nagitapp, MU. YuOapuz (1995). Meiphorpagtasiodu 34:1239-1258. 22. M.A. Kodamuzki (1993) Ttepaz Rpagtasoi. from 14:325-331. at 23. Voopeg.). apa Zepzepibgeppeg M. (1972). Meigobioiodu 2:97-105. 24. risnieg, M. (1987) Vgaiip Kezeagsi 149:279.

Claims (1)

The formula of the invention b5 1. Compound of formula I: Ez EI ' o schu k-t - Her 1 Elen yin V r -o t Z y; By Kk, where t - B: means "(А)п-(СВ'В2)-МАЗВЯ; - Friday, 1 or 2; - And selected from the group containing linear or branched lower alkyl (C.i-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - V' and V? independently selected from the group containing hydrogen, linear or branched lower alkyl(C.4-Cv), linear or branched lower alkenyl(C»-Cv) and linear or branched lower alkynyl(Co-Cv); - B3 and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv), or together they form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M they form optionally (C .-Cv)alkyl- and/or C(Co-Cv)alkenyl substituted 3-7- -linen azacycloalkane or azacycloalkene; - In? independently selected from the group consisting of linear or branched lower alkyl(C1-Cv), linear or 9) branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv), or B? combines with the carbon to which it is attached and the neighboring carbon, forming a double bond; - Cr, Ku, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C--Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co- Св), or Кр, Ку, К, and КК» can independently combine with the carbon to which they are attached and - the neighboring carbon, forming a double bond, or Кр, Ка, Ки K5 can independently form a double /h "E connection with ) or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from cyclohexane, - cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,4-diene, "cyclohexa-1,5-diene , cyclohexa-2,4-diene and - with cyclohexa-2,5-diene, and under the condition that at least one of Ker and Ka is not hydrogen and at least one of K, and K. is not hydrogen, -" and provided that 0-7 is cyclohexane, if at least one of (A) (CB), KZ, B, B», Bp, Ka, B, and K5 is a linear or branched lower alkenyl (C 5-Ce) or linear or branched lower alkynyl(Co-Cv); - and its optical isomers and pharmaceutically acceptable additive salts of acids or bases. c 2. The compound according to claim 1, selected from the group including: 1-ethenyl-3,3,5,5-tetramethylcyclohexylamine, t. 2-(3,3,5,5-tetramethylcyclohexylidene)ethanamine, - 20 1-amino-3,3,5-trimethyl-2-cyclohexene, 1,3,5,5-tetramethyl-2-cyclohexene-1 -amine, and42) 1-allyl-3,3,5,5-tetramethylcyclohexanamine, 1-(3,93,5,5-tetramethylcyclohexylidene)-2-propanamine, 1-(3,3-diethyl-5,5- dimethylcyclohexylidene)-2-propanamine, cis-3-vinyl-1,3,trans-5o-trimethylcyclohexylamine, 22 2-methyl-1-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)- 2-Propanamine, Gee! 1-(1-allyl-3,3,5,5-tetramethylcyclohexyl)piperidine, 2-(1-vinyl-3,3,5,5-tetramethylcyclohexyl-1)ethylamine, where 1-IZ,3,5,5 -tetramethyl-1-(3-methyl-2-butenyl)cyclohexyl|piperidine, 1-III,3,5,5-tetramethyl-1-(2-propynyl)ucyclohexyl|piperidine, 60 2-(1,3,3 ,5,5-pentamethylcyclohexyl)-4-pentenylamine, 3-(3,3,5,5-tetramethylcyclohexylidene)propanamine, 2-methyl-1-(3,3,5,5-tetramethylcyclohexylidene)-2-propanamine, 2 -(3,3,5,5-tetramethylcyclohexylidene)propanamine, M-methyl-1-ethenyl-3,3,5,5-tetramethylcyclohexylamine, 65 M-allyl-1,3,3,5,5-pentamethylcyclohexanamine and their optical isomers and pharmaceutically acceptable addition salts of acids or bases. C. A pharmaceutical composition containing a compound according to claim 1 or claim 2 in combination with one or more pharmaceutically acceptable diluents, excipients and/or carriers. 4. A method of treatment in animals of a condition that is cured by an MMA antagonist, which includes the stage of administering to the animal a certain amount of the compound of formula I: "(A)(СВ 82) 4-MVZ B; - pt, 1 or 2; - A selected from the group containing linear or branched lower alkyl (C.i-Cv), linear or branched lower alkenyl (Co-Cv ) and linear or branched lower alkynyl(Co-Cv); - B' and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl(C.4-Cv), c linear or branched lower alkenyl(C" -Cv) and linear or branched lower alkynyl (Co-Cv); - BZ and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), and) linear or branched lower alkenyl (C »-Cv) and linear or branched lower alkynyl (Co-Cv), or together form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv )alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalc an or azacycloalkene; co - B, Cr, Ka, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C.-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower - alkynyl (So-Sv), or in", Kr, Ka; Ki K5 can independently combine with the carbon to which they are attached and the neighboring carbon, forming a double bond, or Kr, Ku, K, and K5 can independently form a double bond with ) or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from - cyclohexane, cyclohex-1-ene, cyclohex-2-ene, « cyclohex-3-ene, cyclohexa-1,3-diene, - c cyclohexa-1,4-diene, h cyclohexa-1,5-diene, -» cyclohexa-2,4-diene and cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if at least one with "(А)п-(СВ Б), ВУ, В", ВУ, Вр, Ро В, ш- is a linear or branched lower alkenyl(С 2-Св) or a linear or branched lower c alkynyl(Со-Св ); its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective for alleviating the specified condition. -I 20 5. Method of treatment in animals of the condition, where the compound is selected for its immunomodulatory, antimalarial, anti-Vogpa virus or anti-virus effectiveness hepatitis C, with antitrypanosomal effectiveness and against the herpes virus, which includes the stage of administering to the animal a certain amount of the compound of formula I: - B" means -"(А)п-(СВ 82) 4-МВ ЗВ; - pt, 1 or 2; - А is selected from the group containing linear or branched lower alkyl (C.i-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv) - B and B are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C4-Cv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); - B3 and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), linear or branched lower alkenyl ( C»-Cv) and linear or branched lower alkynyl (Co-Cv), or together 70 form alkylene (Co-Cv) or alkenylene (Co-Cv), or together with M form optionally (C 1-Cv)alkyl - and/or (C»-Cv)alkenyl-substituted 3-7--ene azacycloalkane or azacycloalkene; - VU, Kr, Ka, K, and Ke independently selected from the group containing hydrogen, linear or branched lower alkyl (C.- Sv), linear or branched lower alkenyl (Co-Cv) and linear or a branched lower /5 alkynyl (C2-Cv), or B, Kr, Ka Ki Ve can independently combine with the carbon to which they are attached and the neighboring carbon, forming a double bond, or Kr, Ku, K, and K5 can independently form a double bond with ) or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene, cyclohexa-1, 4-diene, cyclohexa-1,5-diene, c and y cyclohexa-2,4-diene and C) cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if at least one of ( A) (СВ), КУ, В", В5, Ро, Во, В, is a linear or branched lower alkenyl (С 2-Св) or a linear or branched lower CO alkynyl (Со-Св); its optical isomers and pharmaceutical acceptable additive salts of acids or bases, which are effective for alleviating the specified condition. 6. A method of treating in animals a condition treatable by an MMOA antagonist selected from the group consisting of excitotoxicity selected from stroke ischemia, trauma, hypoxia, hypoglycemia, glaucoma and hepatic encephalopathy, chronic neurodegenerative diseases selected from Alzheimer's disease, vascular dementia, i.e. Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS neurodegeneration, olivopontocerebellar atrophy of Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome and Creutzfeldt-Jakob disease, other disorders related to long-term plastic changes in the central nervous system, selected from chronic pain, drug tolerance, dependence and addiction (for example, opioid, cocaine, benzodiazepine, nicotine, and alcohol), and epilepsy, tardive dyskinesia, I-0ORA-induced dyskinesia, schizophrenia, condition anxiety, depression, acute pain, spasticity and tinnitus x, which includes the stage of administering to the animal a certain amount of the compound of formula I: that e ' - k 5 ra t. M x -0.720 go and o 55 Bi Kk, where o - B" means -"(A)p-(SV 82) 4-MA ZV; - pt, 1 or 2; 60 - A selected from the group containing linear or branched lower alkyl (C.i-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - B' and B' are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); b - B3 and c? are independently selected from the group containing hydrogen, linear or branched lower alkyl(C4-Cv), linear or branched lower alkenyl(C»-Cv) and linear or branched lower alkynyl(Co-Cv), or together form alkylene(Co-C:o) or alkenylene(Co-C: o), or together with M form optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; - B, Kr, Ka, K, and Ke independently selected from the group containing hydrogen, linear or branched lower alkyl (C.-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv), or in, Cr, Ka; Ki K5 can independently combine with the carbon to which they are attached and an adjacent carbon to form a double bond, or Kr, Ku, K, and K5 can independently form a double bond with ) or U to which they are attached ; provided that Sh-M-M/-X-y-2 is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene, cyclohexa-1, 4-diene, cyclohexa-1,5-diene, cyclohexa-2,4-diene and cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if at least one of "(A)n- (СВ В), ВУ, В", ВУ, Вр, Ро В, is a linear or branched lower alkenyl (Со-Св) or a linear or branched lower alkynyl (Со-Св); its optical isomers and pharmaceutically acceptable additive salts acids or bases that are effective in alleviating the indicated condition. 7. The method of treatment in animals of a condition that is cured by an antagonist of the 5-HT receptor, which includes stage c. Administration of a certain amount of the compound of formula I to the animal: d) where: "-B" means -"(A)n-(СВ 82) 4-MA ZB; - с - пт, 1 or 2; а - А is selected from the group containing linear or branched lower alkyl (C.i-Cv), linear or branched "» lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - V' and V? independently selected from the group containing hydrogen, linear or branched lower alkyl(C.4-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv); ш- - ВЗ Her КЕ" are independently selected from the group containing hydrogen, linear or branched lower alkyl (C-4-Cv), c linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co- Sv), or together form alkylene(Co-C:o) or alkenylene(Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or ve (Co-Cv)alkenyl substituted 3-7-ene azacycloalkane or azacycloalkene; - and 20 - B, Kr, Ka, K, and Ke independently selected from the group containing hydrogen, linear or branched lower alkyl (C.-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv), or c", Cr, Ka Ki K5 can independently combine with the carbon to which they are attached and the adjacent carbon, forming a double bond, or Kr, Ku, K, and K5 can independently form a double bond with ) or U to which they are attached, provided that Sh-M-M/-X-y-2 is selected from (F. cyclohexane, GI cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohexa-1,5-diene, cyclohexa -2,4-diene and 65 cyclohexa-2,5-diene, and provided that 0-7 represents cyclohexane, if at least one of "(A)p-(СВ'B2)-, KU, B" VU, Vr, Vo, V, is a linear or branched lower alkenyl (C 2-Cv) or a linear or branched lower alkynyl (Co-Cv); its optical isomers and pharmaceutically acceptable addition salts of acids or bases that are effective in alleviating the specified condition. 8. The method of treatment in animals of a condition that is cured by an antagonist of neuronal nicotinic receptors, which includes the stage of administering to the animal a certain amount of the compound of formula I: Ez r ' o mi y Shk 1 Kum | ry E. go and By Kk where - B" means "(A)-(СВ 82) -MAZV; - p-t: 0, 1 or 2; - A selected from the group containing linear or branched lower alkyl (C .i-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv); сч » - B' and B? are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), (o) linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv); - VZ Her KE" are independently selected from the group containing hydrogen, linear or branched lower alkyl (C-4-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv), or together they form alkylene (C2-C.0) or alkenylene (Co -С:о), or together with M form an optional (С 1-Св)alkyl- and/or (С»-Св)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; - - VU, Cr, Ka, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C.-Cv), linear or branched lower alkenyl(Co-Cv), and linear or branched lower oy alkynyl (Co-Cv), or в, Кр, Ка Кі K5 can independently combine with the carbon to which they are attached and the neighboring carbon, forming a double bond, or Кр, Ку, К, and Ке can independently to form a double and - connection with ) or U, to which they are attached; provided that Sh-M-M/-X-y-2 is selected from cyclohexane, "cyclohex-1-ene, cyclohex-2-ene, t c cyclohex-3-ene, h cyclohexa-1,3-diene, -» cyclohexa-1,4-diene, cyclohexa-1,5-diene, cyclohexa-2,4-diene and - cyclohexa-2,5-diene, sl and provided that 0-7 represents cyclohexane, if at least one of (А) (СВ), КУ, В", ВУ, Вр, В; В, is a linear or branched lower alkenyl (C 2-Cv) or a linear or branched lower o alkynyl (Co-Cv); -I 20 optical isomers thereof and pharmaceutically acceptable addition salts of acids or bases which are effective in ameliorating said condition.co 9. Method of treating in an animal a condition treatable by a 5-HT antagonist selected from the group consisting of disorders associated with the condition anxiety, depressive disorders, schizophrenia, and treatment of related psychoses, drug and alcohol abuse disorders, cognitive impairment, 22 Alzheimer's disease, Parkinson's disease, cerebellar tremor, migraine, appetite disorders, mucosal colitis (IV) and GF) blue treatment, which includes the stage of administering to the animal a certain amount of the compound of formula I: name) 60 b5 Ez r ' o shku k-t - 1 Elen yin V r -o t Z no By t de t - V: means "(A)p-(СВ'В2)-MAZVYA; - Friday, 1 or 2; - And selected from the group containing linear or branched lower alkyl (C.i-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - V' and V? independently selected from the group containing hydrogen, linear or branched lower alkyl(C.4-Cv), linear or branched lower alkenyl(C»-Cv) and linear or branched lower alkynyl(Co-Cv); - B3 and E7 are independently selected from the group containing hydrogen, linear or branched lower alkyl (C.4-Cv), linear or branched lower alkenyl (C»-Cv) and linear or branched lower alkynyl (Co-Cv), or together form alkylene (Co-C:o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; - B, Cr, Ka, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C.-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl( Co-Cv), or RU, Kr, Ka, K, and Ke can independently combine with the carbon to which they are attached and the neighboring carbon, forming a double bond, or Kr, Ku, K, and K5 can independently combine form double (2,0) connection with ) or U, to which they are attached; what- provided that Sh-M-M/-X-y-2 is selected from cyclohexane, " cyclohex-1-ene, and cyclohex-2-ene, cyclohex-3-ene, - cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohexa-1,5-diene, " cyclohexa-2,4-diene and cyclohexa-2,5-diene, ts and under the condition that 0-7 represents cyclohexane, if at least one of "(A)n-(СВ Б), ВУ, Б", ВУ, Вр, Ро В, "" represents a linear or branched lower alkenyl (C 2-Cv) or a linear or branched lower " alkynyl (Co-Cv); its optical isomers and pharmaceutically acceptable addition salts of acids or bases that are effective for alleviation of the indicated condition. ш- 10. A method of treating in animals a condition treatable by an antagonist of neuronal nicotinic receptors, c selected from the group consisting of Tourette's syndrome, disorders associated with the state of anxiety, schizophrenia, drug abuse, nicotine abuse, cocaine abuse , dyskinesia (Mohryv Nipiipdiup, ve IG-PORA-induced), disorders associated with attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, -I 20 Parkinson's disease and pain, which includes the step of administering to the animal some amount of the compound of formula I: Ж so Kch y ' schu otu o N y yu Pr I U sem B bo shcha z Ya By Kk where 65 - В" means -"(A)p-( SV 82) 4-MA ZV; - Friday, 1 or 2; - And selected from the group containing linear or branched lower alkyl (C.i-Cv), linear or branched lower alkenyl (Co-Cv) and linear or branched lower alkynyl (Co-Cv); - V' and V? independently selected from the group containing hydrogen, linear or branched lower alkyl(C.4-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv); - VZ and in? independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C4-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co-Cv), or together form an alkylene(Co-C :o) or alkenylene (Co-C:o), or together with M form optionally (C .-Cv)alkyl- and/or (Co-Cv)alkenyl-substituted 3-7-ene azacycloalkane or azacycloalkene; - B, Cr, Ka, K, and Ke are independently selected from the group consisting of hydrogen, linear or branched lower alkyl(C.-Cv), linear or branched lower alkenyl(Co-Cv) and linear or branched lower alkynyl(Co -Св), or Ве, Кр, Ка, Ки Ку can independently combine with the carbon to which they are attached and the neighboring carbon, forming a double bond, or Кр, Ку, К, and К5 can independently form a double bond connection with ) or U, to which they are attached; 19 provided that Sh-M-M/-X-y-2 is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohexa-1,3-diene, cyclohexa-1 ,4-diene, cyclohexa-1,5-diene, cyclohexa-2,4-diene and cyclohexa-2,5-diene, c and U and provided that 0-7 represents cyclohexane, if at least one of "( A)n-(СВ В), У, В, ВЗ, Во in ОО is a linear or branched lower alkenyl (C 2-Cv) or a linear or branched lower alkynyl (Co-Cv); its optical isomers and pharmaceutically acceptable additive salts of acids or bases that are effective for alleviating the indicated condition. Mr. 2. 11. Application of the compound of the formula | according to any of claims 4-10 and its optical isomers and pharmaceutically acceptable additive salts of acids or bases in the production of a medicinal product for use in the method according to any of claims 4-10. IF) and - - . and? -i 1 sh» -i IR e) ime) bo b5