RU2152925C1 - Derivatives of aminobicyclo[3,1,0]hexane-2,6-dicarboxylic acid and pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes the novel compounds of the formula (I)

where X means (CH₂)_n; R² means CO₂R⁴; R³ means hydrogen atom or R² means hydrogen atom and R³ means CO₂R⁴; R¹ and R⁴ each means independently hydrogen atom, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, aryl or arylalkyl; n = 1, or their pharmaceutically acceptable salts. The compounds effect on some receptors of excitable amino acids and can be used for treatment of patients with neurological and psychiatric disorders. Also, invention describes pharmaceutical composition containing compound of the formula (I) as an active component and intermediate compounds used for synthesis of compound (I). EFFECT: valuable medicinal properties. 11 cl, 3 tbl, 25 ex

Description

 In mammalian central nervous system (CNS), transmission of nerve impulses is controlled by the interaction between the neurotransmitter, which is secreted by the transmitting neuron, and the surface receptor of the receiving neuron, which causes excitation of this receiving neuron.

 L-glutamate, which is the most common neurotransmitter in the central nervous system, serves as an intermediate in the main pathway of transmission of excitation in mammals and is called the excitatory amino acid (VAC). Receptors that respond to glutamate are called excitatory amino acid receptors (VAC receptors), see Watkins and Evans, Ann. Rev. Pharmacol Toxicol. 21, 165 (1981); Monaghan, Bridges and Cotmon in Ann. Rev. Pharmacd Toxicol. 29, 365 (1989); Watkins, Krogspaard-Larsen and Honore, Trans. Pharm. Sci., 11, 25 (1990). Excitatory amino acids are of great physiological importance, playing a role in a wide variety of physiological processes. In particular, in the long-term preservation of learning and memorizing abilities, in the development of synaptic flexibility, motor control, respiration, cardiovascular regulation, emotional states, and sensory perception.

 Excessive or inappropriate stimulation of excitatory amino acid receptors leads to damage or loss of a nerve cell by a mechanism known as excitotoxicity. It is believed that such a process is an intermediate link in the degeneration of neurons in a wide variety of conditions. The medical consequence of this neural degeneration determines the importance of the therapeutic goal, which is the weakening of these processes of neurological degeneration.

 Excitatory amino acid receptors are divided into two main types. Receptors that are directly associated with the opening of the cationic channels of the cell membranes of neurons are called "ionotropic". Receptors of this type are divided into at least three subtypes, which are determined by the depolarization actions of selective agonists of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy, 5-methylisoxazole-4-propionic acid (AMPK) and kainic acids (CC). The receptor of the second main type is a G-protein or a secondary messenger-bound "metabotropic" excitatory amino acid receptor. This second type is associated with numerous second messenger systems, which leads to improved phosphoinositide hydrolysis, activation of phospholipase D, an increase or decrease in CAMP formation, and changes the functioning of ion channels [see Schoepp and Conn at Trends in Pharmacol. Sci. , 14, 13 (1993)]. Apparently, the receptors of both types not only serve as an intermediate link in the normal synaptic transmission of excitation along the path of excitation, but also take part in the modification of synaptic connections during development and throughout life [see. Schoepp, Backaert and Sladecrek, Trends in Pharmacol. Sci., 11,508 (1990); McDonald and Johnson, Brain Research Reviews 15.41 (1990)].

 Metabotropic glutamate receptors are an extremely heterogeneous family of glutamate receptors that are associated with numerous secondary messenger pathways. Typically, the role of these receptors is to modulate the presynaptic release of glutamate and the postsynaptic sensitivity of the neuron cell to glutamate excitation. Metabotropic glutamate receptors (mGluR) are pharmacologically subdivided into two subtypes. The receptors of one group are positively associated with phospholipase C, which causes the hydrolysis of cellular phosphoinositides (P1). The receptors of this first group are called P1-linked metabotropic glutamate receptors. The receptors of the second group are negatively associated with adenylcyclase, which prevents the forskolin-initiated accumulation of cyclic adenosine monophosphate (cAMP) [see Schoepp and Conn Trends in Phamacol. Sci., 14, 13 (1993)]. Receptors in this second group are called CAMP-linked metabotropic glutamate receptors. Agonists of CAMP-associated metabotropic glutamate receptors should be useful in the treatment of acute and chronic neurological diseases and psychiatric diseases.

 Recently, compounds have been discovered that act on metabotropic glutamate receptors, but do not affect ionotropic glutamate receptors. (1S, 3R) -1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3P-ACPD) is an agonist of P1-linked and CAMP-linked metabotropic glutamate receptors [see Schoepp, Johnson, True, and Monn at Eur. J. Pharmacol., 207, 351 (1991); Schoepp, Johnson and Monn. J. Neurochem 58, 1184 (1992)]. Recently, (2S, 3S, 4S-2- (carboxycyclopropyl) -glycine (L-SCCH-1) has been described as a selective agonist of a CAMP-linked metabotropic glutamate receptor, but at elevated concentrations, this compound is active at P1-linked metabotropic receptors [ see NaRagawa et al. in Eur. J. Pharmacol., 184, 205 (1990); Hayashi, et al. in Br.J. Pharmacol. 107, 539 (1992); Schoepp et al. in J. Neurochem ., 63, pp. 769-772 (1994)].

где X обозначает группу (CH₂)_n; R² обозначает группу СО₂R⁴, а R³ обозначает водородный атом или же R² обозначает водородный атом, а R³ обозначает группу CO₂R⁴; каждым из R¹и R⁴ независимо от другого обозначен водородный атом, C₁ - C₁₀ алкил. C₁-C₁₀, алкенил, арил или арилалкил; а n равно 1; или к их фармацевтически приемлемым солям.In accordance with the present invention, there are provided compounds that selectively act on negatively coupled CAMP-linked metabotropic glutamate receptors. More specifically, the present invention relates to compounds of formula I

where X is a group (CH ₂ ) _n ; R ² is a CO ₂ R ⁴ group, and R ³ is a hydrogen atom, or R ² is a hydrogen atom, and R ³ is a CO ₂ R ⁴ group; each of R ¹ and R ^4, independently of the other, designates a hydrogen atom, C ₁ - C ₁₀ alkyl. C ₁ -C ₁₀ alkenyl, aryl or arylalkyl; and n is 1; or their pharmaceutically acceptable salts.

 The present invention also provides pharmaceutical compositions comprising a compound of formula 1 in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.

 The compounds proposed in accordance with this invention can be obtained in the method of acting on cAMP-associated metabotropic glutamate receptors, as well as in the methods of treating neurological disorders or psychiatric diseases that are associated with excitatory amic acid receptors, according to which the introduction of a compound of formula 1 Examples of neurological disorders that are treated with a compound of formula 1 include cerebral disorders resulting from surgery uu with cardiopulmonary bypass and grafting, cerebral ischemia (e.g., as a result of attack and cardiac arrest); spinal cord injury; head injury; Alheimer's disease; Huntington's chorea; amyotrophic lateral sclerosis; AIDS-induced dementia muscle cramps; migraine; urinary incontinence; cramps perinatal oxygen deficiency; hypogluicemic neuronal disorder; drug tolerance, withdrawal and cessation of medication, such as opiates, benzodiazepines, nicotine, cocaine or ethanol, smoking cessation; eye damage and retinopathy; disorders of consciousness; disease of unknown origin and Parkinson's disease caused by drugs; vomiting cerebral edema; chronic pain sleep disorders Tourette's syndrome; attention deficit disorders and delayed dyskinesia. Examples of psychiatric disorders that are treated with a compound of Formula 1 include schizophrenia, fear, and related illnesses (e.g., panic attacks and stress-related illnesses), depression, bipolar disorders, psychosis, and compulsive compulsive disorders.

где X обозначает группу (CH₂)_n; n обозначает 1; R^2a обозначает группу СО₂R^4a, а R^3a обозначает водородный атом, или R^2a обозначает водородный атом, а R^3a обозначает группу CO₂R^4a; а R^4a обозначает водородный атом или карбоксиблокирующую группу; и их солям.Compounds that can be used to synthesize compounds of formula 1 are also provided in accordance with the present invention. More specifically, the present invention relates to compounds of the formula

where X is a group (CH ₂ ) _n ; n is 1; R ^2a is a CO ₂ R ^4a group, and R ^3a is a hydrogen atom, or R ^2a is a hydrogen atom, and R ^3a is a CO ₂ R ^4a group; and R ^4a represents a hydrogen atom or a carboxy blocking group; and their salts.

где X обозначает группу (CH₂)_n; n обозначает 1; R^2a обозначает группу CO₂R^4a, а R^3a обозначает водородный атом, или R^2a - обозначает водородный атом, а R^3a - обозначает группу CO₂R^4a; а R^4a обозначает водородный атом или карбоксиблокирующую группу;
2) реакция соединения формулы

где значения символов X, R^2a и R^3a определены выше, с цианидом щелочного металла и аммониевой солью и гидролиз полученного промежуточного продукта как указано выше (1) или
3) гидролиз соединения формулы

где R^1a обозначает карбоксизащитную группу, а значения символов X, R^2a и R^3a определены выше, и
4) необязательное удаление карбоксизащитной группу и
5) необязательная этерификация одной или обеих карбоксильных групп и
6) необязательное разделение диастереомеров и/или выделение энантиомеров и
7) необязательное получение фармацевтически приемлемой соли соединения формулы 1.The present invention also provides a process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, which comprises:
1) hydrolysis of a compound of the formula

where X is a group (CH ₂ ) _n ; n is 1; R ^2a is a CO ₂ R ^4a group, and R ^3a is a hydrogen atom, or R ^2a is a hydrogen atom, and R ^3a is a CO ₂ R ^4a group; and R ^4a represents a hydrogen atom or a carboxy blocking group;
2) the reaction of the compounds of formula

where the meanings of the symbols X, R ^2a and R ^{3a are} defined above, with alkali metal cyanide and ammonium salt and hydrolysis of the obtained intermediate product as described above (1) or
3) hydrolysis of a compound of the formula

where R ^1a denotes a carboxy-protecting group, and the meanings of the symbols X, R ^2a and R ^{3a are as} defined above, and
4) optional removal of a carboxy protecting group; and
5) optional esterification of one or both carboxyl groups and
6) optional separation of diastereomers and / or isolation of enantiomers and
7) the optional preparation of a pharmaceutically acceptable salt of a compound of formula 1.

The term “C ₁ -C ₁₀ alkyl” is intended to mean a straight, branched or cyclic chain containing from one to ten carbon atoms. Typical straight or branched C ₁ -C ₁₀ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert. butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, heptyl, n-octyl, 2,2-dimethylhexyl, 2,5-dimethylhexyl, 2-methylheptyl, 4-methylheptyl, 2,2,4-trimethylpentyl, 2,3,4-trimethylpentyl, nonyl, 3,5,5-trimethylhexyl, decyl, 3, 7-dimethyloctyl and the like. The meanings of the term “C ₁ -C ₁₀ alkyl” also include the meanings of the terms “C ₁ -C ₆ alkyl” and “C ₁ -C ₄ alkyl”. Typical cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A class of typical C ₁ -C ₆ alkyl groups includes methyl, ethyl, n-propyl. isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.

The term “C ₁ -C ₁₀ alkenyl” is intended to mean straight or branched unsaturated alkyl chains containing from two to ten carbon atoms and having from one to several carbon-carbon double bonds, in particular dienes and trienes. This class also includes both E ₇ and Z-isomers. Typical radicals of this class include vinyl, allyl, allenyl, 1-butenyl, 2-butenyl, 2-methyl-1-propenyl, 3-butenyl., 2-methyl-2-propenyl. butadienyl, 1-pentenyl, 2-pentenyl, 2-methyl-2-butenyl., 4-pentenyl, 3-methyl-2-butenyl. 3-methyl-1,2-butadienyl, 3-hexenyl, 2-hexenyl, 4-methyl-3-pentenyl, 4-hexenyl, 5-hexenyl, 3-methyl-1-penten-3-yl, 4-methyl 3Z-pentenyl, 6-methyl-5-hepten-2-yl, 7-octenyl. 1-octene / 3-yl, 3-nonenyl. 2,4-dimethyl-2,6-heptane-dienyl. 3,7-dimethyl-6-octenyl, 5-decenyl, 9-decenyl, 2,6-dimethyl-7-octenyl and the like. The meanings of the term “C ₂ -C ₁₀ alkenyl” also encompass the meanings of the term “C ₂ -C ₆ alkenyl."

 The term “stereoisomeric compound” is used to denote the optical isomer of the compound of formula 1. Typical stereoisomeric compounds include 1S, 2S, 5R, 6S-, isomer, 1R, 2R, 5S, 6R- isomer, 1S, 2R, 5R, -6R- isomer, 1R, 2S, 5S is the 6R isomer, 1S, 2S, 5R, 6R isomer. 1R, 2R, 5S, 6S isomer, 1S, 2R, 5R-6R isomer and 1R, 2S, 5S, 6S isomer.

 The term “diastereomeric compound” refers to a mixture of two stereoisomers (non-superimposable) of a compound of formula 1. The class of typical diastereomeric compounds includes 1SR, 2SR, 5SR, 6SR-mixture, 1SR, 2RS, 5RS, 6SR — mixture, 1SR, 2SR 5RS, 6RS mixture and 1SR, 2RS 5RS, 6RS mixture. The preferred diastereomeric compound is 1SR, 2SR-5RS, 6SR-mixture. The preferred ethantiomer is the 1S, 2S-5R, 6S isomer.

The term “carboxy protecting group” is used herein to mean one of the ester derivatives of a carboxy group, which is commonly used to block or protect a carboxy group when reactions are carried out involving other functional groups. Protection of carboxyl groups is generally described in McOmie, Protecting Groups in Organic Chemistery, Plenum Press, NY, 1973; and Greene and Wuts, Protecting Groups in Organic Synthesis 2nd edition, Tohn Wiley and Sons, NY, 1991. Examples of such carboxy protecting groups include methyl, ethyl, methoxymethyl, methylthiomethyl. triphenylmethyl, benzyl. 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl. 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, benzhydryl, tert. butyl, tert.-amyl, trityl, trimethylsilyl, tert. butyl-dimethylsilyl, allyl, 1- (trimethylsilylmethyl) prop-1-en-3-yl and the like. Particularly preferred carboxy protecting groups are C ₁ -C ₆ alkyl groups, in particular methyl and ethyl. The term “protected carboxyl” refers to a carboxyl group that has a carboxy protecting group.

 The term "nitrogen protecting group" is used herein to mean substituents of amino groups that are commonly used to block or protect a functional amino group when the reaction is carried out with the participation of other functional groups. Protection of amino groups is generally described in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973; and Greene and Wuts, Protecting Groups in Organic Synthesis 2nd edition, John Willey and Sons, NY, 1991. Examples of azo blocking groups include benzyl, tert. butyl, allyl, triphenylmethyl, tert.-butyldimethylsilyl, triphenylsilyl, formyl, trityl, phthalimido group, trichloroacetyl. chloroacetyl, phthaloyl, 2-nitrophenoxyacetyl, benzyloxycarbonyl. methoxycarbonyl, 2-methylbenzyloxycarbonyl, tert.-butoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like. The term "protected amine" refers to a primary or secondary amine containing a nitrogen blocking group.

The term “C ₁ -C ₄ alkoxy group” refers to groups such as methoxy, ethoxy, n-propoxy, isopropoxy-n-butoxy, sec-butoxy and tert. Butoxy. The term “halogen atom” refers to fluorine, chlorine, bromine or iodine atoms.

The term "alkoxycarbonyl" refers to a carboxyl group including a C ₁ -C ₆ alkyl group bonded through an oxygen atom to a carbonyl carbon atom. Typical representatives of groups of this type include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl. tert.-butoxycarbonyl and the like.

 A preferred alkoxycarbonyl group is methoxycarbonyl.

The term “substituted phenyl” as used herein refers to a phenyl group substituted with one or two substituents selected from the group consisting of halogen atoms, hydroxy, cyano, nitro groups, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy groups, alkoxycarbonyl, protected carboxyl, carboxymethyl, oxymethyl. amine, protected amine, aminomethyl and trifluoromethyl. Examples of a substituted phenyl group include 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3, 4-dibromophenyl, 3-chloro 4-fluorophenyl, 2-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dioxophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-ethoxyphenyl, 4-carboxyphenyl, 4- (hydroxymethyl) phenyl, 4-aminophenyl, 4-propyl-phenyl, 4-butylphenyl, 4-tert-butylphenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2, 6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4,6-trifluorophenyl, 2-trifluoromethylphenyl, 2-chloro-5-trifluoromethy lphenyl, 2,4-bis- (trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5 -dimethyl-4-hydroxyphenyl, 4-hydroxy-3- (oxymethyl) phenyl, 2-amino-5-methylphenyl, 4-amino-3-trifluoromethylphenyl, 3-amino-4-hydroxyphenyl, 2-methyl-4-nitrophenyl , 4-methoxy-2-nitrophenyl, 2,4-dinitrophenyl, 3-cyano-4-nitrophenyl and the like.

The term “aryl” is used to mean groups such as phenyl, substituted phenyl, and naphthyl. The term “arylalkyl” means a C ₁ -C ₄ alkyl group that has one or more aryl groups. Typical examples of groups of this latter type are benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl. 4-phenylbutyl, 2-methyl-2-phenylpropyl, (4-chlorophenyl) methyl, (2,6-dichlorophenyl) methyl, bis- (2,6-dichlorophenyl) methyl, (4-hydroxyphenyl) methyl, (2, 4-dinitrophenyl) methyl, triphenylmethyl, (4-methoxyphenyl) diphenylmethyl, bis- (4-methoxyphenyl) methyl, alpha-naphthyldiphenylmethyl, bis- (2-nitrophenyl) methyl and the like.

 The term "affecting" refers to a compound of formula 1, which acts as an agonist at the excitatory amino acid receptor. The term “excitatory amino acid receptor” refers to a metabotropic glutamate receptor, that is, a receptor that binds to cellular effectors via CTP binding proteins. The term "CAMP" - associated metabotropic glutamate receptor "refers to a metabotropic receptor that is associated with inhibition of adenylate cyclase activity.

 The term "neurological disorder" refers to both acute and chronic "neurodegenerative conditions", including cerebral disorders resulting from surgery with artificial blood circulation and transplantation, cerebral ischemia (for example, an attack resulting from cardiac arrest), spinal cord injury, trauma scalp, Alheimer’s disease, Huntington’s chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, perinatal oxygen deficiency, hypoglycemic neuron distribution triad, eye damage and retinopathy, impaired consciousness, disease of unknown origin and Parkinson's disease caused by drugs. This term also covers other neurological conditions that are caused by glutamate dysfunction, including muscle cramps, migraines, urinary incontinence, drug tolerance, withdrawal and withdrawal of drugs, such as opiates, benzodiazepines, nicotine, cocaine or ethanol, smoking cessation, vomiting, head swelling brain, chronic pain, sleep disturbances, cramps, Tourette syndrome, disorders manifested in lack of attention and delayed dyskinesia.

 The term “psychiatric disorders” encompasses both acute and chronic psychiatric conditions, including schizophrenia, fear and related illnesses (for example, panic attacks and stress-related cardiovascular diseases), depression, bipolar disorder, psychosis and obsessive compulsive disorders

The scope of the present invention encompasses pharmaceutically acceptable salts of the compounds of formula 1. These salts can exist in combination with the acidic or main part of the molecule and can exist in the form of acid addition salts, addition salts of primary, secondary, tertiary or quaternary ammonium bases, alkali metal salts or alkaline earth salts metals. Typically, acid addition salts are prepared by reacting an acid with a compound of formula 1. Alkali metal salts and alkaline earth metal salts are usually prepared by reacting a compound in the form of a hydroxide salt of a desired metal and a compound of formula 1 in which R ¹ and / or R ⁴ is a hydrogen atom.

 The acids that are usually used to obtain such salts include mineral acids, in particular hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, as well as organic acids such as paratoluenesulfo, methanesulfonic acids, oxalic, para-bromophenyl sulfonic acid, carbonic, succinic , citric, benzoic and acetic acids and related mineral and organic acids. Thus, the class of these pharmaceutically acceptable salts includes sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, ammonium, acid phosphates, secondary acid phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebatsaty, fumarates, hippurates, maleates, butyn-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates. dinitrobenzoates, oxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, alpha-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, sulfanesulfonates, 1-sulfonates, salts of magnesium, tetramethylammonium, potassium, trimethylammonium, sodium, methylammonium, calcium and the like salts.

Абсолютную стереохимическую конфигурацию этого наиболее предпочтительного энантиомера определяют как 1S, 2S, 5R, 6S. Таким образом, рамками настоящего изобретения охватываются стереоизомерные соединения формулы 1, характеризующиеся этой самой предпочтительной стереохимической конфигурацией, смеси энантиомеров, содержащие компоненты с такой предпочтительной стереохимической конфигурацией (включая сюда рацематы), и смеси диастереомеров, содержащие компоненты с такой предпочтительной стереохимической конфигурацией.The compounds of formula 1 proposed by the present invention have four asymmetric carbon atoms. Asymmetric centers are a substituted carbon atom carrying amino and carboxyl groups, a carbon atom at the site of which R ² and R ^{3 are} attached, and two carbon atoms at the junction of the condensed rings. Asymmetric carbon atoms are respectively at positions 2, 6, 1, and 5. Thus, the compounds of the present invention can exist as substantially pure optical isomers, a mixture of two enantiomers (including racemic modifications), and a mixture of two diastereomers. When R ² is a CO ₂ R ⁴ group and each of R ', R ³ and R ⁴ is a hydrogen atom, the biologically active and most preferred stereoisomer, as determined by receptor binding assays, is characterized by positive optical rotation (AD). X-ray single-crystal analysis made it possible to establish the structure of this most preferred enantiomer, which made it possible to reveal the relative stereochemical configuration shown below:

The absolute stereochemical configuration of this most preferred enantiomer is defined as 1S, 2S, 5R, 6S. Thus, the scope of the present invention encompasses stereoisomeric compounds of formula 1 characterized by this most preferred stereochemical configuration, mixtures of enantiomers containing components with such a preferred stereochemical configuration (including racemates), and mixtures of diastereomers containing components with such a preferred stereochemical configuration.

Although it is believed that all compounds of formula 1 of the present invention selectively act on negatively connected CAMP-linked metabotropic glutamate receptors, some compounds of the invention are preferred for such use. In a preferred embodiment, R ² is a CO ₂ R ⁴ group, R ³ is a hydrogen atom, and each of R ¹ and R ^{4 is} independently a hydrogen atom, C ₁ -C ₆ alkyl, aryl or arylalkyl. Typical compounds of this preferred group of compounds of formula 1 include 2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylic acid, dimethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, diethyl-2-aminodicyclo [ 3.1.0] hexane-2,6-dicarboxylate, dibutyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, dihexyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, diphenyl- 2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate and dibenzyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate. Certain compounds of the present invention are more preferred for use on CAMP-linked metabotropic glutamate receptors. In a more preferred embodiment, each of R ¹ and R ^{4 is} independently a hydrogen atom, C ₁ -C ₄ alkyl, aryl or arylalkyl. Typical compounds of this more preferred group of compounds include 2-aminodicyclo [3.1.0] -hexane-2,6-dicarboxylic acid, dimethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, diethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, dibutyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, diphenyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate and dibenzyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate.

Some compounds are most preferred for use on exposure to CAMP-linked metabotropic glutamate receptors. In a most preferred embodiment, each of R ¹ and R ^4, independently of the other, is a hydrogen atom or C ₁ -C ₄ alkyl. Typical compounds of this group of most preferred compounds include 2-aminodicyclo [3.1.0] -hexane-2,6-dicarboxylic acid, dimethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, diethyl-2-aminodicyclo [3.1.0.] - hexane-2,6-dicarboxylate, dibutyl-2-aminodicyclo [3.1.0] hexane-2, 6-dicarboxylate and dipropyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate .

The most preferred compounds of formula (1) are (+) - 2-aminodicyclo [3.1.0] -hexane-2,6-dicarboxylic acid, its C ₁ -C ₄ alkyl, aralkyl and aryl esters and their pharmaceutically acceptable salts.

Although it is contemplated that all compounds of formula X of the present invention can be used to synthesize compounds of formula 1, some of these compounds are preferred. In a preferred embodiment, R ^2a is a CO ₂ R ^4a group, and R ^3a is a hydrogen atom. In a more preferred embodiment, R ^4a represents a hydrogen atom or a C ₁ -C ₆ alkyl group, for example an ethyl group.

Compounds of formula 1 of the present invention are typically synthesized by cyclopropanation of 2-cycloalken-1-one, that is, compounds of formula II wherein X is as defined above for compounds of formula 1. Compounds of formula 1 in which R ³ represents a hydrogen atom and R ² denotes a group of CO ₂ R ⁴ receive as shown in scheme 1.

Обычно проводят реакцию соединения формулы II с метилдиметилсульфонийбромидом с защищенной карбоксильной группой с получением дициклического соединения формулы III, у которых R^4a обозначает карбоксилзащитную группу. Реакцией Штреккера или Бухерера-Бергса проводят превращение этого соединения в аминокислоту с последующими гидролизом и этерификацией с получением соединений формулы IV в виде смеси изомеров. Эту изомерную смесь разделяют с получением соединений формулы V и формулы VI. Эти соединения далее гидролизуют с получением соединений формулы I, у которых R² обозначает группу CO₂R⁴, а R¹ и R⁴ обозначают водородные атомы.Scheme I

Typically, a compound of formula II is reacted with a protected carboxy group methyldimethylsulfonium bromide to produce a dicyclic compound of formula III in which R ^4a is a carboxyl protecting group. The Strecker or Bucherer-Bergs reaction converts this compound into an amino acid, followed by hydrolysis and etherification to give compounds of formula IV as a mixture of isomers. This isomeric mixture is separated to give compounds of formula V and formula VI. These compounds are then hydrolyzed to give compounds of formula I in which R ² is a CO ₂ R ⁴ group and R ¹ and R ⁴ are hydrogen atoms.

More specifically, 2-cycloalken-1-one is reacted with (protected carboxyl) methyldimethylsulfonium bromide to give a bicyclic intermediate of formula III. This cyclopropanidation is conveniently carried out in an organic solvent in the presence of an amine base. A class of solvents suitable for such a reaction includes acetonitrile, dichloromethane, benzene, toluene and xylene, more preferably acetonitrile or dichloromethane. Amine bases suitable for use during this reaction include non-nucleophilic bases, in particular, such as 1,8-diazadicyclo [5.4.0] undec-7-ene, pyridine and collidine. The preferred amine base for use in carrying out such a reaction is 1,8-diazadicyclo [5.4.0] undec-7-en. In a preferred embodiment, carboethoxymethyldimethylsulfonium bromide is reacted with an amine base to give ethyl (dimethylsulfuranylidene) acetate in situ. The resulting mixture was treated with 2-cycloalken-1-one. Examples of 2-cycloalken-1-ones include 2-cyclopenten-1-one, 2-cyclohexen-1-one, 2-cyclohepten-1-one and 2-cycloocten-1-one. Such a reaction is usually carried out at a temperature of from about 25 to 50 ^° C., more preferably at a temperature of from about 25 to 30 ^° C. Typically, such a reaction is completed in about 18 hours to three days.

Bicyclic intermediate III is converted into a bicyclic amino acid by the Strecker or Bucherer-Bergs reaction followed by hydrolysis of the intermediate products Krauch and Kunz, Organic Name Reactions, 76 (1964), see references therein. In a preferred embodiment, the bicyclic ketone III is reacted with an aqueous solution of potassium cyanide or sodium cyanide and ammonium carbonate to produce hydantoin intermediates. Such a reaction is usually carried out in an alcoholic solvent, in particular in an ethanol or methanol. The reaction is usually carried out at a temperature of from about 25 ^° C. to the boiling point of the solvent under reflux, preferably at about 50 ^° C. After about an 18-hour period, this reaction is usually completed. Isomeric hydantoins can be isolated and purified as described below. In a preferred embodiment, the mixture of isomeric hydantoins is hydrolyzed using sodium hydroxide and subsequently subjected to complex esterification without isolation or purification to a compound of formula V or formula VI. This hydrolysis is usually carried out at the boiling point of the solvent under reflux for about 15 to 20 hours.

The hydrolysis products, a mixture of isomeric compounds of the formula I, in which R ¹ represents a hydrogen atom, are preferably esterified prior to separation of the diastereomers and enantiomers. When the carboxy-protecting group is removed during hydrolysis, a dibasic acid ester is subsequently obtained. A solution of a carboxylic acid or dicarboxylic acid in alcohol, for example in methanol, ethanol, isopropanol or n-butanol, is treated with thionyl chloride and refluxed. As a rule, before adding thionyl chloride, the solution of the hydrolysis product is cooled to about 0 ^° C. The esterification is usually completed after about 48 hours.

 Diastereomeric products, compounds of formula V and formula VI, are separated using standard techniques. Preferred separation methods include crystallization and / or chromatography. The compound of formulas V and VI can be selectively crystallized by the preparation of acid addition salts, in particular oxalate. This salt is obtained by treating with an ethyl acetate solution containing a mixture of compounds of formulas V and VI with oxalic acid and ethanol. To preferentially crystallize one of the diastereomers, an additional amount of ethanol can be added. The implementation of this procedure allows to obtain crystalline material enriched in one of the isomers, and a filtrate (mother liquor) enriched in the other isomer. Such compounds can be further purified using chromatography, in particular chromatography on silica gel.

If necessary, the compounds of formulas V and VI are hydrolyzed and the carboxyl-protecting group is removed to give compounds of the formula I in which R ¹ and R ⁴ are hydrogen atoms. These compounds are typically hydrolyzed by treating a solution of a compound of formula V or formula VI in an organic solvent, in particular tetrahydrofuran, with an aqueous base, in particular sodium hydroxide. Such hydrolysis is usually carried out at room temperature; approximately 18 hours are required to complete it. Carboxyl-protecting groups are removed in accordance with standard synthesis methods (see McOmie and Greene and Wuts).

The enantiomers of each pair of diastereomers of intermediates V and VI are separated using standard resolution techniques [see Jacques, Collet. and Wilen, Enantiomers, Racemates, and Resolutions. (1981)]. The preferred method for resolving enantiomers provides for the preparation of diastereomeric salts between racemic modifications and optically active (chiral) resolving agents (Jaques, Collet and Wilen, chapter 5). Compounds of formulas V and VI in which R ^4a represents a carboxyl protecting group can be separated using acid chiral resolving agents. Examples of suitable acidic chiral resolving agents include (+) - camphoric acid, (+) - and (-) - dibenzoyl tartaric acid, diacetone ketogluconic acid, lazalocidic, (+) and (-)-mandelic acid, (+) - and ( -) - malic acid, (+) - and (-) - quinic acid, (+) - and (-) - tartaric acid, (+) - di-p-toluene-D-tartaric acid and (-) - di -p-toluene-L-tartaric acid. Preferred acid release agents for the separation of compounds of formulas V and VI in which R ^4a represents a carboxyl protecting group are (+) - di-p-toluoyl-D-tartaric acid and (-) - di-p-toluoyl-L-tartaric acid . Compounds of formulas V and VI in which R ^4a represents a hydrogen atom can be separated using basic chiral resolving agents. An example of a basic chiral resolving agent is (8) -1-phenyl-ethylamine.

 In another embodiment, the bicyclic compound of formula III is converted into a mixture of diastereomeric hydantoins as shown in Scheme II.

Проводят реакцию бициклического промежуточного продукта III, полученного, как описано с раствором цианистого калия или цианистого натрия и карбонатом аммония, получая диастереомерные гидантоиновые промежуточные соединения формулы VII и формулы VIII. Эту реакцию как правило ведут в смеси воды с таким спиртом, как метанол или этанол. Реакцию ведут при температуре приблизительно от 55 до 60^oC и ее обычно завершают по истечении примерно от 18 ч до 4 дней. Диастереомерные продукты разделяют с применением стандартных методик, в частности, кристаллизацией и/или хроматографией. В предпочтительном варианте соединения формул VII и VIII разделяют кристаллизацией.Scheme II

The bicyclic intermediate III is prepared as prepared with a solution of potassium cyanide or sodium cyanide and ammonium carbonate to give diastereomeric hydantoin intermediates of formula VII and formula VIII. This reaction is usually carried out in a mixture of water with an alcohol such as methanol or ethanol. The reaction is carried out at a temperature of from about 55 to 60 ^° C. and is usually completed after about 18 hours to 4 days. Diastereomeric products are separated using standard techniques, in particular crystallization and / or chromatography. In a preferred embodiment, the compounds of formulas VII and VIII are separated by crystallization.

Compounds of formulas VII and VIII in which R ^4a represents a hydrogen atom can be separated using a basic chiral resolving agent. An example of a basic chiral resolving agent is (R) -1-phenylethylamine.

The hydantoin intermediate of formulas VII or VIII is converted to a compound of formula I, wherein R ¹ and R ⁴ are hydrogen atoms, by hydrolysis. The hydantoin group and ester group are hydrolyzed using an aqueous base such as sodium hydroxide or an aqueous acid, in particular hydrochloric acid. This hydrolysis is usually carried out at a temperature of from about 100 to 150 ^° C. The resulting compound of formula I is purified using ion exchange chromatography.

Compounds of formula I in which R ² is a hydrogen atom and R ³ is a CO ₂ R ^4a group are prepared as shown in Reaction Scheme III.

Проводят реакцию 2-циклоалкен-1-она и диметилсульфуранилиденацетата с защищенным карбоксилом с получением изомерных бициклических промежуточных продуктов III и 2Y. Это циклопропанирование проводят в органическом растворителе при температуре приблизительно от 45 до 85^oC. Класс подходящих растворителей охватывает бензол, толуол, ксилол и ацетонитрил. В предпочтительном варианте реакцию проводят в бензоле при 50^oC. Диастереомерные продукты разделяют с использованием хроматографии на силикагеле. Конверсию соединения формулы IX в соединения формулы I проводят с использованием методик, которые описаны выше для конверсии соединений формулы III.Scheme III

The reaction of 2-cycloalken-1-one and dimethylsulfuranylideneacetate with a protected carboxyl is carried out to give isomeric bicyclic intermediates III and 2Y. This cyclopropanation is carried out in an organic solvent at a temperature of from about 45 to 85 ^° C. The class of suitable solvents includes benzene, toluene, xylene and acetonitrile. In a preferred embodiment, the reaction is carried out in benzene at 50 ^° C. The diastereomeric products are separated using silica gel chromatography. The conversion of the compounds of formula IX to compounds of the formula I is carried out using the procedures described above for the conversion of compounds of the formula III.

 Compounds of formula III in which X is methylene can be prepared as shown in Reaction Scheme IV.

Проводят реакцию соединения формулы XI с (защищенный карбоксил)метилдиметилсульфоний бромидом с получением соединения формулы XII, у которого R^4a обозначает карбоксилзащитную группу. Эту реакцию обычно проводят в соответствии с методом, аналогичным тому, который описан выше для циклопропанировании соединения формулы II. Далее, полученное соединение формулы XII превращают в соединение формулы XIII выдержкой при повышенной температуре, например при температуре в интервале от 160 до 500^oC, предпочтительнее от 180 до 300^oC. В результате такой выдержки из соединения формулы XII высвобождается циклопентадиен. Эту стадию удобно осуществлять в атмосфере инертного газа, в частности азота, и в среде инертного органического растворителя, например дихлорбензола. Далее превращают полученное соединение формулы XIII в соединение формулы III восстановлением, например гидрогенизацией в присутствии палладия на угле. Такое восстановление удобно проводить при температуре в интервале от 0 до 50^oC. Класс приемлемых для такого восстановления растворителей включает спирты, в частности этанол, сложные эфиры, в частности этилацетат, ароматические углеводороды, в частности толуол, и такие амиды, как диметилформамид.Scheme IV

A compound of formula XI is reacted with (protected carboxyl) methyldimethylsulfonium bromide to produce a compound of formula XII in which R ^4a is a carboxyl protecting group. This reaction is usually carried out in accordance with a method similar to that described above for cyclopropanation of the compounds of formula II. Further, the resulting compound of formula XII is converted to a compound of formula XIII by exposure to an elevated temperature, for example, at a temperature in the range from 160 to 500 ^° C., more preferably from 180 to 300 ^° C. As a result of such exposure, cyclopentadiene is released from the compound of formula XII. This step is conveniently carried out in an inert gas atmosphere, in particular nitrogen, and in an inert organic solvent, for example dichlorobenzene. The resulting compound of formula XIII is then converted to a compound of formula III by reduction, for example by hydrogenation in the presence of palladium on charcoal. Such a reduction is conveniently carried out at temperatures ranging from 0 to 50 ^° C. The class of solvents suitable for such a reduction includes alcohols, in particular ethanol, esters, in particular ethyl acetate, aromatic hydrocarbons, in particular toluene, and amides such as dimethylformamide.

 It is obvious that the use of an optically active compound of the formula XI as a starting material makes it possible to obtain an optical active compound of the formula III.

 The compounds of formula XIII are believed to be novel; they are an additional aspect of the invention.

 Compounds of formula XI (including their optically active forms) can be prepared according to the method described by Klunder et al., Tetrahedron Lett., 1986, 27, 2543 and Takano et al., Synlett 1991, 636.

Compounds of formula I in which R ¹ and R ⁴ are C ₁ -C ₁₀ , C ₂ -C ₁₀ alkenyl, aryl or arylalkyl are prepared from the corresponding compounds in which R ¹ and R ⁴ are hydrogen atoms. These compounds are usually prepared using standard synthetic techniques. In a typical example, the compounds of formula I are reacted in which R ¹ and R ⁴ are hydrogen atoms with C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ , alkenyl, aryl or arylalkyl alcohol in the presence of an acid to give the corresponding ester. This reaction is usually carried out with an excess of alcohol in the presence of a catalytic amount of concentrated sulfuric acid.

Compounds of formula I in which the values of R ¹ and R ^{4 are} not the same can be obtained from a dibasic acid in which R ¹ and R ^{4 are} hydrogen atoms using standard organic synthesis techniques. For example, for this purpose, one can resort to chemical methods that were developed for the selective functionalization of the carboxyl groups of glutamic and aspartic acids. Alternatively, by selecting a carboxyl protecting group for a compound of formula X which is stable under hydrolysis conditions for the hydantoin group, carboxyl groups can be selectively manipulated.

 The compounds of formula I of the present invention are agonists of certain metabotropic excitatory amino acid receptors. Specifically, the compounds of formula I are agonists of negatively linked CAMP-linked metabotropic glutamate receptors. Thus, another aspect of the present invention relates to a method for exposing a mammalian excitatory amino acid receptor, which comprises administering to a mammal that requires modulated neurotransmission of an excitatory amino acid, a pharmaceutically effective amount of a compound of formula I. The term “pharmaceutically effective amount” is used to mean such amounts of a compound of the invention that is capable of acting on excitatory amino acid receptors . Due to this effect, the compound of the invention exhibits an agonist action. When a compound of the invention acts as an agonist, the interaction of this compound with an EaA receptor resembles a reaction of the interaction of such a receptor with its natural ligand (i.e., L-glutamate).

 The specific dose of the compound administered to the body is determined in each case by specific circumstances, including the particular compound administered to the body, the route of administration to the body, the condition of the patient when such treatment is applied, and the like. Such compounds can be administered in a variety of ways, including oral, rectal through the skin, subcutaneously, intravenously, intramuscularly or intranasally. In addition, such a compound can be introduced into the body by continuous infusion. A typical daily dose of an active compound of the present invention is from about 0.001 mg / kg to about 100 mg / kg. Preferred daily doses are from about 0.05 to 50 mg / kg, more preferably from about 0.1 to 20 mg / kg.

 It was found that excessive or inappropriate stimulation of the transmission of the excitatory amino acid leads to effects on various physiological functions. It is believed that the compounds of formula 1 of the present invention are capable of treating various neurological disorders associated with this condition in mammals, including acute neurological disorders, in particular, cerebral disorders resulting from surgery with artificial blood circulation and transplantation, cerebral ischemia ( for example, as a result of an attack and cardiac arrest), spinal cord injury, head injury, perinatal oxygen deficiency and hypoglycemic female neural disorder. The compounds of formula 1 are believed to have the ability to treat a variety of chronic neurological disorders, in particular, such as Alheimer's disease, Huntington’s chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, eye damage and retinopathy, disorders of consciousness, disease of unknown origin and Parkinson’s disease caused by medicines.

 The compounds of formula 1 of the present invention are also believed to have the ability to treat a wide variety of other neurological disorders in mammals that are associated with glutamate dysfunction, including mouse spasms; cramps migraine; urinary incontinence, psychosis; drug tolerance, withdrawal and discontinuation of medication (e.g., opiates, benzodiazepines, nicotine, cocaine or ethanol); smoking cessation; fear and related illnesses (for example, panic attacks and stress-related illnesses); vomiting cerebral edema; chronic pain sleep disorders Tourette's syndrome; attention deficit disorders and delayed dyskinesia.

 The compounds of the present invention are agonists of cAMP-linked metabotropic glutamate receptors. These compounds negatively bind via the receptor to adenylcyclase inhibiting the formation of cyclic adenosine monophosphate. The compounds of formula I of the present invention therefore have the ability to treat a wide variety of psychiatric diseases, in particular such as schizophrenia, fear and related diseases (e.g., panic attacks and stress-related diseases), depression, bipolar disorder, psychosis and obsessive compulsive disorders.

Experiments were performed to demonstrate the ability of compounds of formula I to affect excitatory amino acid receptors. The affinity of such compounds for metabotropic glutamate receptors has been demonstrated by selective substitution of (1S, 3R) -1-sensitive amino cyclopentane-1,3-dicarboxylic acid [ ³ H] glutamate, which binds to rat brain cell membranes. The binding of [ ³ H] glutamate ([ ³ H] glu) was performed using untreated rat forebrain membranes as described by Schoepp and True [see Schoepp and True, Neurosciense Lett, 145, 100-104 (1992); Wright, MeDonald, and Shoepp, J. Neurochem., 63, 938-945 (1994). The concentration of the compounds of formula I, which inhibits 50% binding (IC ₅₀ ) or the percentage substitution of [ ³ H] Glu at a concentration of the compounds of formula I of 10 μm or 100 μM, are presented in table. 1.

All connections. 3, 6, 7 and 8 are dicarboxylic acids. In general, it was found that during the test for receptor binding, ester derivatives (those compounds of formula 1 in which one or both of R ¹ and R ⁴ are non-hydrogen atoms) were found to be inactive. However, it is believed that such compounds in vivo are able to hydrolyze to the corresponding acid and, therefore, can act as prodrugs. It must be borne in mind that in accordance with the present invention, active dicarboxylic acids are provided, as well as all prodrug forms which are capable of forming an active active acid in vivo.

The compounds of formula 1 are effective in acting on CAMP-linked metabotropic glutamate receptors. Typical compounds were tested for their ability to attenuate forskolin-stimulated cAMP production in rat hippocampus and rat cerebral cortex using techniques described by Schoepp and Johnson L [see Schoepp and Johonson Neurochem Int., 22, 277-283 (1993)]. The results of such experiments are summarized in table. II
The ability of compounds of Formula 1 to treat fear or related disorders can be demonstrated using fear-potentiated flinch in the super-cascade labyrinthine fear models described respectively in Davis Psychopharmacology 62: 1; 1979 and Lister Psychopharmacol., 92: 180-185; 1987.

 In the model of fear-potentiated startle, animals are affected by such a neutral stimulus as light (a conditioned stimulus), together with such a stimulus that causes a negative reaction as shock (an unconditioned stimulus). After the elaboration of the conditioned reflex, when animals are exposed to a loud sound stimulus, in the event that the stimulus causing the fright is preceded by light, an enhanced jerking reflex is manifested.

 The super-cascade labyrinth model is based on the natural negative emotions that rodents cause height and open spaces.

 Diazepam and buspirong hydrochloride, which clinical have established themselves as tranquilizers, are effective in easing the fear (enhanced jerking reflex) associated with light exposure of the fear-potent jerking model and easing the fear of open spaces in a super-cascade labyrinth model.

From the kennel, Harlan Sprague-Dawley, Cumbreland, Indiana, USA, male Long Evans rats (180-400 g each) and Swiss NIH male mice (18-35 g each) and animals were acclimated for at least 3 days prior to testing. Animals were kept at 23 ± 2 ^o C and relative humidity from 30 to 70%. They were fed rodent-tested food on Purina and were given unlimited water. The daily regimen consisted of 12 hours of light period and 12 hours of darkness, with darkness falling at about 18 hours 00 minutes.

 Before use, the test compounds were dissolved in a carrier from purified water and the 5N solution was neutralized. sodium hydroxide to a pH of 7-8. Diazepam (Sigma Chemical Company, St. Louis, Missouri) was suspended in purified water using a dropwise added Tween 80 product. Control animals were given the appropriate vehicle.

 Potentiated by a startle fear. SL-LAB cameras (San Diego Instruments, San Diego, California) were used to develop a conditioned reflex, as well as to obtain and fix jerking reflexes. To achieve potentiated jerking reflexes, we used the technique of developing a conditioned reflex according to the Pavlov method. For the first 2 days, rats were placed in dark start chambers in which shock nets were installed. After a 5-minute acclimatization period, each animal was exposed to a 1-milliampere electric shock (500 μs), which was preceded by a 5-second exposure to light (15 W), which remained on for the duration of the electric shock. During each procedure for generating a conditioned reflex, they were exposed 10 times to light and electric shock, animals were injected with a solution of the test compound in water through a gastric tube and the jerking test procedures were continued. In order to minimize the influence of the initial fast phase of getting used to the stimulus, at the beginning of the procedure, a block of 10 consecutive actions was performed with a sound stimulus causing fright (110 dB, without combination with light). This was followed by 20 alternative experiments using only sound or sound preceded by light. Excluding the initial block of experiments, the amplitudes of the startle reflexes for each type of experiment (only one sound against the light + sound) on each animal were averaged for the entire test procedure. The data presented reflects the difference between the results obtained using only one sound and light + sound. All parameters are summarized in table. III.

 Automated super cascade maze. The design of the cascade maze was based on the design that was introduced for mice by Lister (1987). The entire labyrinth was made of transparent plexiglass. This labyrinth consisted of two open sections (30 x 5 x 0.25 cm) and two closed sections (30 x 5 x 15 cm). To give structure to the floor in each maze was corrugated. The sections passed from the central platform and turned relative to any other at an angle of 90 degrees. The labyrinth was elevated to a height of 45 cm above the floor and lit with red light. Along each of the sections of the labyrinth, individual infrared photocells were mounted in order to control activity in the closed, open areas or poking nose. Mice were individually placed on the central platform of the maze, the results of counting the number of closed sections, open sections and poking with the nose were recorded (poking with a head only into an open section from a closed section of the maze) and the data was used as a measure of the entrances to the sections and the time spent in different sections of the maze five minute test period.

 Oral administration of compound 6 into the body led to a significant increase in activity in open areas at doses of 1, 3, and 10 mg / kg. The number of poking nose increased significantly at a dose of 3 mg / kg. At any dose of compound 6, the calculated activity parameters in closed areas did not undergo noticeable changes.

 The ability of compounds of formula 1 to protect warm-blooded animals from the effects of withdrawal or discontinuation of drug administration can be demonstrated using a sound model of fear. In this model, animals are given a medicine (nicotine or diazepam), and then the medicine is stopped. This withdrawal of the drug causes an increase in the startle reaction to sound stimuli. Then, test compounds are introduced into the animal organism in order to determine whether they are able to attenuate the increased startle reaction.

 Long Evans rats (200-400 g, Harlan Spraque Dawley, Colubus, Indiana) were kept individually in a controlled environment with a 12-hour light-dark cycle and free access to food (Purina Rodent Chow) in water. Animals were anesthetized with isoflurane and they were implanted subcutaneously with Olzet osmotic pumps (Olzet Corporation).

 When introduced into the body, the test compound was dissolved in a carrier, which was purified water, and a 5N solution was neutralized. sodium hydroxide to a pH of 7-8. Diazepam (Sigma Chemical Company, St. Louis, Missouri) was suspended in a carrier which consisted of 40% 300 polyethylene glycol, 10% ethanol, 2% benzyl alcohol, 1% 80 product and 47% purified water. Nicotine (Research Byokemicals Inc., Neutic, Mass.) Was dissolved in saline. Control animals were given the appropriate vehicle.

Nicotine withdrawal. The pumps were filled so that they secreted nicotine (6 mg / kg / day subcutaneously), diazepam (10 mg / kg / day subcutaneously), test compound (0, 1, 3, 10 mg / kg subcutaneously) or vehicle. 12 days after subcutaneous implantation of the pumps, the rats were anesthetized with isoflurane and the pumps were removed. During drug withdrawal (after pump removal) using San Diego Instruments start-up cameras (San Diego, California), the individual animals startled sound response (peak amplitude, V _max ). Animal intimidation techniques consisted of a 5-minute adaptation period with a sound level of 70 ± 2 dB, immediately followed by a 25-fold exposure to a sound stimulus (sound level - 120 ± 2 dB, pulse duration - 50 μs) with 8-second intervals between pulses. Further, with respect to each procedure, the peak jerking amplitudes for all 25 stimulus pulses were averaged and all data were presented as values for the entire procedure. Sound startle reactions were evaluated daily 1, 2, 3, 4, or 5 days after drug withdrawal. The baseline of the startle reaction was evaluated before removing the pump on day 12.

Compared with the animals of the control group, which were given water, the sound reaction of startle increased noticeably during the first three days after the cessation of chronic use of nicotine by animals. Animals to which a dose of nicotine was replaced by intraperitoneal administration of doses of 0.03 mg / kg or more did not exhibit the same increased tremor response as animals which did not produce any nicotine replacement. The pretreatment with compound 6 also provided a blockade of the dosing-dependent jerking response caused by withdrawal. Compared to animals of the control group that were given nicotine (ED ₅₀ = 0.7 mg / kg ip), a significant weakening of the increased fright was evident with the oral administration of a dose of compound 6 of 3 mg / kg.

Cancel diazepam. In the first four days after the cessation of the constant administration of diazepam in comparison with animals of the control group, which were given only a carrier, the rattling reaction to a sound stimulus increased markedly. Replacing the intraperitoneal dosing of diazepam at 3 and 10 mg / kg did not block the increased startle reaction and, in some cases, further increased the ability to respond, indicating tolerance. Substitution in rats that were injected intraperitoneally with 30 mg / kg of diazepam daily 60 minutes before the startle reaction was evaluated showed an increased ability to react after stopping the administration of diazepam in the period from the 1st to the 4th day in comparison with the control animals groups given diazepam. The pretreatment with compound 6 blocked the expected increase in the startle reaction that followed after the cessation of the administration of diazepam. Doses of 0.1 and 0.3 mg / kg of the orally administered compound 6 significantly attenuated the increased startle in comparison with the reaction, which was observed in animals of the control group (ED ₅₀ = 0.1 mg / kg orally).

 Before administration to the body based on the compounds of the present invention, it is preferable to formulate the compositions. Thus, another aspect of the present invention is a pharmaceutical composition which comprises a compound of formula 1 in combination with one or more pharmaceutically acceptable carriers, diluents or excipients. The proposed pharmaceutical compositions are prepared according to known methods using well-known and readily available components. In the process of preparing the compositions of the present invention, the active ingredient is usually mixed with a carrier or diluted with a carrier, or introduced into a carrier, the preparation may be in the form of a capsule, sachet, in a paper container or made of another material. In the case where the carrier acts as a diluent, it may be a solid, semi-solid or liquid material that acts as a carrier, drug environment or medium for the active component. Such compositions can be prepared in the form of tablets, pills, powders, lozenges, sachets, starch capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosol preparations, ointments containing, for example, up to 10 wt.% Active substance, soft and hard gelatin capsules, suppositories, sterile injectable solutions, plasters, hypodermic implants and powders in sterile packaging.

 Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, aqueous , methyl and propyloxybenzoates, talc, magnesium stearate, stearic acid and mineral oil. Such compositions may further comprise lubricants, wetting agents (surfactants), emulsifiers and suspending agents, preservatives, sweeteners, flavoring and aromatic additives. The compositions of the invention can be prepared in such a way as to provide fast, continuous or delayed release of the active substance after administration to the patient using methods that are known in the art.

 Such compositions are preferably formulated in a unit dosage form, each dose comprising from about 1 to 500 mg, more preferably from about 5 to 200 mg, of the active ingredient. The term "single dosage form" is used to refer to a physically discrete unit acceptable for use as single doses for humans and other mammals, each such unit containing a predetermined amount of active substance, calculated to achieve the desired therapeutic effect, in combination with an acceptable pharmaceutical carrier, diluent or filler. The following examples of compositions are provided for illustrative purposes only and are by no means intended to limit the scope of the invention (see composition 1-8 at the end of the text after the tables).

The compounds of the present invention and methods for their synthesis are further illustrated by the following examples. These examples are not to be construed as limiting the scope of the present invention. All experiments were carried out under excess pressure of dry aeroton or argon. In all cases, except as specifically indicated, all solvents and reagents were ready-made and used without further processing. Dry tetrahydrofuran (THF) was processed by distillation with sodium or sodium benzophenone ketyl before use. The proton nuclear magnetic resonance spectrum ( ¹ H-NMR) was obtained using a GE QE-300 spectrometer at a frequency of 300.15 MHz, an AM-500 Brucker spectrometer at a frequency of 500 MHz, or an AC-200P Brucker spectrometer at a frequency of 200 MHz. Free-atom bombardment mass spectroscopy (IMSA) was performed using a VG-ZAB-2SE instrument. Mass spectroscopy (MSF) of the desorption region was carried out using a VG 70SE or Varian MAT 731 instrument. Optical rotation was measured using a Perkin-Elmer 241 polarimeter. Chromatographic separation in a Waters Prep 500 LC was usually performed using a linear solvent gradient as indicated in the text. . The completion of the reaction was usually determined by thin layer chromatography (TLC). Thin layer chromatography was performed using E. Merck Kieselgel 60 F ₂₅₄ plates with a thickness of 0.25 mm and other dimensions of 5 cm x 10 cm. The spots were determined using UV and chemical detection (plates soaked in cerium (IV) solution ammonium molybdate 75 mg of ammonium molybdate and 4 g of tetravalent cerium sulfate in 500 ml of 10% aqueous sulfuric acid and then heated on a hot plate).

 Flash chromatography was performed as described in Still et al., J. Org. Chem., 43, 2923. Elemental analysis for carbon, hydrogen, and nitrogen was performed in a 440 analyzer from Control Environmental Corporation or performed at the Universidad Complutense analytical center ( Facultad de Farmacia, Madrid, Spain). Melting points were determined in open glass capillaries on a Gallencamp hot-water melting device or on a Buchi melting-temperature instrument and were not adjusted. The numbers in brackets given after the name of the compound serve as a reference to the serial number of the compound.

Production Example 1. - Carboethoxymethyldimethylsulfonium bromide
A solution of 265 g of ethyl bromoacetate and 114 g of dimethyl sulfide in 500 ml of acetone was stirred at room temperature. After three days by filtration of the reaction mixture, the title compound of the example was isolated. Melting point: 88-90 ^o C.

Example 1. (1SR, 5RS, 6SR) -ethyl-2-hydroxydicyclo [3.1.0] hexane-6-carboxylate
A suspension of 45.5 g of carboethoxymethyldimethylsulfonium bromide in 350 ml of toluene was treated with 30.2 g of 1,8-diazadicyclo [5.-4.0] undec-7-ene. The resulting mixture was stirred at room temperature. After one hour, the reaction mixture was treated with 19.57 g of 2-cyclopenten-1-one. After an additional 18 hours, the reaction mixture was added in 1N. a solution of sodium chloride in hydrochloric acid. The resulting mixture was extracted with diethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a ethyl acetate-hexanes mixture with a linear gradient of 10 to 50% ethyl acetate, whereby 22.81 g of the title compound was obtained. Melting point: 36-38 ^o C.

Mass spectrum: m / z = 168 (M ⁺ ).

Elemental analysis data for C ₉ H ₁₂ O ₃ :
Calculated: C - 64.27, H - 7.19
Found: C - 64.54, H - 7.11
Example 2. (1SR, 2RS, 5RS, 6SR) -diethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate (1) and (1SR, 2SR, 5RS, 6SR) -diethyl-2-aminodicyclo [ 3.1.0] hexane-2,6-dicarboxylate (2)
A solution of 22.81 g of the compound obtained in Example 1 in 200 ml of ethanol was treated with an aqueous solution of 9.71 g of potassium cyanide and 21.2 g of ammonium carbonate in 200 ml of water. The resulting mixture was heated to a temperature of about 50 ^° C. After about 18 hours, the reaction mixture was allowed to cool to room temperature and it was treated with 16.2 g of sodium hydroxide. The resulting mixture was kept at the boiling temperature under reflux. After approximately 18 hours, the reaction mixture was allowed to cool to room temperature, and then it was cooled to 0 ^° C. By adding concentrated hydrochloric acid, the pH of the cold mixture was adjusted to 1. This mixture was concentrated to dryness in vacuo. The residue was dissolved in ethanol, cooled to 0 ^° C. and treated with 80.6 g of thionyl chloride. The resulting mixture was kept at the boiling temperature under reflux. After approximately 48 hours, the reaction mixture was concentrated in vacuo to dryness. The residue was treated with 1N. solution, sodium hydroxide and the resulting mixture was extracted with diethyl ether. The combined ether extracts were dried over potassium carbonate, filtered and concentrated in vacuo to give 24.6 g of a mixture of the title compounds.

Example 3. - (1SR, 2SR, 5RS, 6SR) -diethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarbonate (2)
A solution of 20.71 g of the compounds obtained according to the above in Example 2 in 200 ml of ethyl acetate was treated with a solution of 15.46 g of oxalic acid in 50 ml of ethanol. The resulting mixture was stirred at room temperature. After one hour, the reaction mixture was treated with an additional 50 ml of ethanol. After 18 hours, the mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was treated with 1N. sodium hydroxide solution and the resulting mixture was extracted with diethyl ether. The combined ether extracts were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a mixture of methylene chloride with 5% ammonium hydroxide and methanol (97: 3), to obtain 15.41 g of the title compound. Mass spectrum: m / z = 242 (M + H).

Elemental analysis data for C ₁₂ H ₁₉ NO ₄ :
Calculated: C - 59.74, H - 7.94, N - 5.81
Found: C - 59.78, H- 8.13 N - 5.77
Example 4. - (1SR, 2SR, 5RS, 6SR) -2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylic acid (3)
A solution of 3.1 g of the compound obtained according to the above in example 3, in 25 ml of 2N. a solution of sodium hydroxide and 25 ml of tetrahydrofuran was stirred at room temperature. After approximately 18 hours, tetrahydrofuran was removed in vacuo and the pH of the resulting solution was adjusted to 9. The title compound was purified by ion exchange chromatography (BiO-Rad AGl-X8), eluting with 50% aqueous acetic acid, to give 2, 12 g of product. Melting point:> 250 ^o C (decomposed). Mass spectrum: m / z = 186 (M + H).

Elemental analysis data for C ₈ H ₁₁ NO ₄ :
Calculated: C - 51.89, H - 5.99, N - 7.56
Found: C - 51.74, H - 6.15, N - 7.45
Example 5. - The hydrochloride salt of (1SR, 2SR, 5RS, 6SR) -diethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate (2).

A solution of 2.41 g of the compound obtained in Example 3 in 75 ml of diethyl ether was stirred at room temperature while passing gaseous hydrochloric acid over the surface of the solution until further salt formation ceased. After an additional five minutes, the salt was removed by filtration, washed with cold diethyl ether, and dried in vacuo at 60 ^° C. for approximately 18 hours to obtain 2.75 g of the title compound. Melting point: 189-191 ^o C.

 Mass spectrum: m / z = 242 (M + H).

Elemental analysis data for C ₁₂ H ₂₀ ClNO ₄ :
Calculated; C - 51.89, H - 7.26, N - 5.04
Found: C - 52.03, H - 7.48, N - 5.06
Example 6. - (-) - Diethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate (4)
A solution of 6.56 g of the racemic mixture of the compounds obtained in Example 3 in 100 ml of ethyl acetate was treated with a solution of 12.0 g of (+) - di-P-toluoyl-D-tartaric acid in 100 ml of ethyl acetate. After cooling overnight at room temperature, the crystalline solid was removed by filtration and dried, yielding 14.7 g of material. By cooling the filtrate to 0 ^° C., an additional amount of crystalline solid was obtained. The combined crystalline solids were dissolved in hot ethyl acetate containing 2-propanol in an amount sufficient to completely dissolve. After cooling to 0 ^° C., crystalline solid material was isolated by filtration to obtain 2.3 g of a solid product, the enantiomeric excess of which was ≥ 95%. Separation of the salt between an aqueous solution of sodium bicarbonate and ethyl acetate gave the product in the form of a free base. The organic phase was separated, dried over potassium carbonate, filtered and concentrated in vacuo to give 0.77 g of the title compound.

 Mass spectrum: m / z = 242 (M + H).

Optical rotation: α _D = -5.15 ^° (c = 1, EtOH).

Elemental analysis data for C ₁₂ H ₁₉ NO ₄ :
Calculated: C - 59.74, H - 7.94, N - 5.81
Found: C - 59.68, H - 8.13, N - 5.58
Example 7. - (+) - Diethyl-2-aminodicyclo [3.1.0.] Hexane-2,6-dicarboxylate (5)
The mother liquors from the experiment of Example 6 were combined and concentrated in vacuo. The conversion of the acid addition salt to the free base was carried out by partitioning between an aqueous solution of sodium bicarbonate and ethyl acetate. The organic phase was separated, dried over potassium carbonate and concentrated in vacuo to give 3.7 g of an oil-like product. This oil-like product was treated with 7.14 g of (-) - P-toluoyl-L-tartaric acid in 100 ml of ethyl acetate. After standing at room temperature overnight, the crystals were collected by filtration and dried. Crystalline solids were dissolved in hot ethyl acetate containing 2-propanol in an amount sufficient to completely dissolve. After cooling to 0 ^° C., the crystals were isolated by filtration to obtain 2.25 g of the title compound, the enantiomeric excess of which was ≥ 95%. The compound indicated in the title of the example, in the form of a free base was obtained almost identically to the above in the amount of 0.74 g.

 Mass spectrum; m / z = 242 (M + H).

Optical rotation: α _D = -7.22 ^° (c = 1, EtOH)
Elemental analysis data for C ₁₂ H ₁₉ ClNO ₄ :
Calculated: C - 59.74, H - 7.94, N - 5.81
Found: C - 59.81, H - 7.88, N - 5.76.

Example 8. - (+) - 2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylic acid (6)
A solution of 0.69 g of the compound obtained in Example 6 in 10 ml of tetrahydrofuran was treated with 10 ml of 1N. sodium hydroxide solution and the resulting mixture was intensively stirred at room temperature. After several days, the compound indicated in the title of the example was isolated by anion exchange chromatography (BiO-Rad AGl-X8), eluting with a 50% aqueous solution of acetic acid, to give 0.53 g of the product indicated in the title of the example.

 Mass spectrum: m / z = 186 (M + H).

Optical rotation: α _D = 21.32 ^° (c = 1, 1N hydrochloric acid).

Elemental analysis data for C ₈ H ₁₁ NO ₄ • 1.25H ₂ O:
Calculated; C - 46.26, H - 6.55, N - 6.74
Found: C - 46.68, H - 6.47, N - 6.49
Example 9. - (-) - 2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylic acid (7)
The compound indicated in the title of the example was prepared essentially identical to the above in Example 8 from the compound described in Example 7 (0.59 g). After a few days, the compound indicated in the title of the example was isolated by anion exchange chromatography (BiO-Rad AGl-X8), eluting with a 50% aqueous solution of acetic acid, to give 0.45 g of the product indicated in the title of the example.

 Mass spectrum; m / z = 186 (M + H).

Optical rotation α _D = -22.72 ^° (c = 1, 1N hydrochloric acid).

Elemental analysis data for C ₈ H ₁₁ NO ₄ • H ₂ O:
Calculated: C - 47.29, H - 6.45, N - 6.89
Found: C - 47.50, H - 6.62, N - 6.31
Example 10. - (1SR, 2SR, 5RS, 6RS) -2-aminodicyclo- [3.1.0] - hexane-2,6-dicarboxylic acid (8)
The title compound was prepared from (1SR, 2SR, 5RS, 6RS) diethyl-2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylate, essentially as described in Examples 3 and 4 above.

Example 11. - Hydrochloride (+) - diethyl-2-aminodicyclo [3.-1.0] hexane-2,6-dicarboxylate
A stream of anhydrous gaseous hydrogen chloride at 0 ^° C. was passed over the surface of a solution of the compound of Example 6 in 75 ml of anhydrous diethyl ether until a white precipitate stopped. The resulting suspension was stirred at room temperature for 2 hours. Then the reaction mixture was diluted with 100 ml of diethyl ether and the solid material was filtered off in vacuo. This solid was washed with 250 ml of diethyl ether and dried at 70 ^° C. in vacuo for 4 hours to obtain 2.32 g (8.4 mmol., 77%) of the title compound. Melting point = 138-140 ^o C.

 Mass spectrum: = 242 M + 1.

Elemental analysis data for C ₁₂ H ₂₀ ClNO ₄ :
Calculated: C - 51.89, H - 7.26, N - 5.04
Found: C - 51.61, H - 7.32, N - 4.99
[α] = +35.52 ^° (c = 0.09, water).

Example 12. - Ethyl ether (+) - [1R- (1a, 1aα, 1bβ, 2b, 5a, -5aβ, 6aα) - 1, 1a, 1b, 2,5,5a, 6,6a - octahydro-6- oxo-2,5-methancycloprom [a] inden-1-carboxylic acid
A suspension of 8.46 g (36.9 mmol.) Of carboethoxymethyldimethylsulfonium bromide in 27 ml of acetonitrile was treated with 5.52 ml (36.9 mmol.) Of 1,8-diazadicyclo [5.4.0] undec-7-ene at room temperature under nitrogen flow. . After stirring for 1 h, the resulting yellow mixture was treated with 3.60 g (24.6 mmol.) (3aR) -3aα.4,7, aα-tetrahydro-4α, 7α-methane-1H-inden-1-one in solid condition and in separate portions for 3 minutes The brown reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched by the addition of 13 ml of 5% hydrochloric acid, the mixture was diluted with 50 ml of brine and washed with 3 portions of 50 ml of methyl tert-butyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give 5.98 g of a brown oil-like product. Chromatography (100 g of silica gel for flash chromatography, a mixture of hexanes with ethyl acetate, initially 8: 1, and then 2: 1 crude oily product gave 5.0 g (88% yield) of the title compound of the example in the form a colorless oil-like product, which, as determined by high pressure liquid chromatography, was the only diastereomer. [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +112 ^° (c = 1.39, methanol); RF = 0.55 (hexanes / ethyl acetate in a 2: 1 ratio); IR ^- spectrum (chloroform); 2982 (W), 2938 (W), 1720 (S), 1276 (m), 1185 (m), 1048 (w) cm ^-1 ; ¹ H-NMR spectrum (CDCl ³ , δ): 6.18 (dd. 1H, J = 5.6, 2.9 Hz), 6.07 (dd, 1H, J = 5.6, 2.9 Hz), 4.14 (g, 2H, J = 7.1 Hz), 3.24 (brs, 1H), 3.13 (brs 1H), 2.86 (dd, 1H, J = 6.9, 4.1 Hz), 2.64 (dd, 1H, J = 6.9, 5.1 Hz), 2.21-2.16 - (m, 2H), 1.88 (t, 1H, J = 3.0 Hz), 1.57 and 1.37 (AB quartet, 2H, J = 8.5 Hz), 1.26 (t, 3H, J = 7.1 Hz); ¹³ C-NMR spectrum (CDCl ₃ , δ): 213.31, 170.78, 135.59, 134.16, 61.56, 51.47, 51.17, 46.45 (2 carbon atoms), 44.20, 39.76, 32.75, 25.76, 14.56.

Elemental analysis data for C ₁₄ H ₁₆ O ₃ :
Calculated: C - 72.39, H - 6.94
Found: C - 72.53, H - 7.08
Example 13. Ethyl ether (+) - [1 (R), 5 (S), 6 (R)] - dicyclo [3.1.0] hex-3-en-2-one-6-carboxylic acid
A solution of 4.89 g (21.1 mmol.) Of the product of Example 12 in 14 ml of dry dimethyl sulfoxide was maintained at the boiling temperature while stirring and purging with nitrogen (bubbler under the surface) to distill the released cyclopentadiene for 24 hours. The reaction mixture was cooled to room temperature temperature, diluted with 100 ml of methyl tert-butyl ether and washed once with 50 ml of water. The aqueous layer was washed once with 25 ml of methyl tert. butyl ether and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow solid. This crude cyclopentenone was crystallized from a mixture of hexanes with methyl tert. butyl ether to give 1.91 g (55% yield) of the title compound. Melting point: 96-98 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +251 (c = 1.12, methanol); R _f = 0.49 (hexanes / ethyl acetate in a ratio of 2: 1); IR (potassium bromide); 2997 (W), 1728 (S), 1747 (S), 1696 (S), 1292 (m), 1266 (S), 1190 (S), 1177 (S) cm ^-1 ; ¹ H-NMR spectrum (CDCl ₃ , δ): 7.61 (dd, 1H, J = 5.6, 2.5 Hz), 5.74 (d, 1H, J = 5.6 Hz), 4 15 (q, 2H, J = 7.1 Hz), 2.96-2.94 (m, 1H), 2.62 (br, 1H, J = 3.9 Hz), 2.26 (t, 1H, J = 2.8 Hz); 1.27 (t, 3H, J = 7.1 Hz); ¹³ C-NMR spectrogram (CDCl ₃ δ): 203.56, 168.28, 159.96, 129.99, 61.70, 46.19, 30.39, 29.28, 14.49.

Elemental analysis data for C ₉ H ₁₀ , O ₃ ;
Calculated: C - 65.05, H - 6.07
Found; C - 64.78, H - 6.24
Example 14. - Ethyl ether (-) - [1 (R), 5 (S), 6 (R)] - dicyclo [3.1.0] hexan-2-one-6-carboxylic acid
A solution of 1.73 g (10.4 mmol.) Of the product of example 13 in 35 ml of 95% ethanol in a stream of nitrogen was treated with 87 mg (5 wt.%) Of 10% palladium on charcoal. The flask was purged with hydrogen and stirring was continued in a hydrogen atmosphere (balloon pressure) for 5 hours, with an additional 35 mg (2 wt.%) Of 10% palladium on carbon added over this period of time. The mixture was stirred in a hydrogen atmosphere for another 50 minutes. The flask was purged with nitrogen and the catalyst was removed by filtration through celite, washing with ethyl acetate. The filtrate and washings were concentrated in vacuo to give 1.75 g of a yellow solid. This crude solid material was crystallized from a mixture of hexanes with methyl tert. butyl ether to obtain 1.38 g (79% yield) of the title compound. Melting point: 63-65 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -60 ^° (c = 1.34, methanol); P = 0.49 (hexanes / ethyl acetate in a 2: 1 ratio); IR (potassium bromide): 2987 (W), 1722 (S), 1410 (m), 1193 (S), 1009 (m), 827 (m) cm ^-1 ; ¹ H-NMR spectrum (CDCl ₃ , δ): 4.16 (q, 2H, J = 7.1 Hz), 2.52 (q, 1H, J = 4.9 Hz), 2.29-2 22 (m, 2H), 2.17-2.00 (m, 4H), 1.28 (t, 3H, J = 7.1 Hz); ¹³ C-NMR spectrum (CDCl ₃ , δ): 212.07, 170.80, 61.64, 36.17, 32.30, 29.59, 26.91, 22.87, 14.56.

Elemental analysis data for C ₉ H ₁₂ O ₃ :
Calculated: C - 64.27, H - 7.19
Found: C - 64.10, H - 7.31
Example 15. - Ethyl ether (+) - [1 (R), 2 (P), 5 (S), 6 (R), 5 '(R)] - 2-spiro-5'-hydantoindicyclo [3.1.0 ] hexane-6-carboxylic acid
A mixture of 1.20 g (7.13 mmol.) Of the product of example 14 with 511 mg (7.85 mmol.) Of potassium cyanide and 1.37 g (7.13 mmol.) Of ammonium carbonate in 7.1 ml of 95% ethanol and 2.9 ml of water were stirred at 36 ^° C. for 10 hours and at room temperature for 13 hours. The turbid yellow reaction mixture was cooled to 0 ^° C. and diluted with 7.8 ml of cold water. After stirring for 1.5 hours, a white solid was collected and washed twice with 5 ml of cold water. The solid was dried in vacuo to give 1.17 g (69% yield) of the title compound as a single diastereomer, as determined by high performance liquid chromatographic analysis. Melting point: 247-249 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +23 ^° (c = 1.05, methanol); IR (potassium bromide): 3504 (m), 3262 (m), 2983 (W), 2766 (W), 1771 (m), 1723 (S), 1415 (m), 1182 (W) cm ^-1 , H NMR spectrum (DMSO-d ₆ , δ): 10.58 (S, 1H), 7.93 (S, 1H), 4.06 (q, 2H, J = 7.1 Hz), 2.08 2.01 (S, 1H), 1.94-1.83 (m, 4H), 1.79 (dd, 1H, J = 13.9, 8.5 Hz), 1.40-1.33 (m, 1H); 1.20 (t, 3H, J = 7.1 Hz); ¹³ C-NMR spectrum (DMSO-d ₆ , δ): 178.30, 172.62, 157.01, 69.52, 61.04, 33.86, 30.37, 28.27, 26.49 , 20.95, 14.93.

Elemental analysis data for C ₁₁ H ₁₄ N ₂ O ₄ :
Calculated: C - 55.46, H - 5.92, N - 11.76
Found: C - 55.76, H - 5.95, N - 11.84
Example 16. - (-) - [1 (R), 2 (R), 5 (S), 6 (R)] - 2-aminodicyclo [3.1.0] hexane-2,6-dicarboxylic acid
A solution of 976 mg (4.10 mmol.) Of the product of Example 15 in 8.2 ml of a 3N sodium hydroxide solution was kept under reflux with stirring for 24 hours. After cooling to room temperature, the reaction mixture was transferred directly to an ion exchange column (filled 50 g of BiO-Rad AG1-X8 acetate resin prepared by washing with 50 ml of a 1N sodium hydroxide solution, followed by 50 ml of water, followed by 50 ml of a 1N sodium hydroxide solution after the reaction was introduced), eluting with a mixture of water and acetic acid in the correlation The solution is 1: 1, taking as a result 50-milliliter fractions. Fractions 2 and 3, which contained the product, were combined and concentrated in vacuo to give 770 mg of a white solid. This solid material was suspended in 4 ml of water and filtered, washing once with 4 ml of water. The solid was dried in vacuo at 40 ^° C. to give 634 mg (76% yield) of the title compound as a white powder. IR (potassium bromide): 3235 (br, S), 2971 (m), 2016 (br, W), 1694 (m), 1613 (S), 1509 (m), 1237 (m) cm ^-1 ; ¹ H-NMR spectrum - (trifluoroacetic acid -d, δ): 2.76-2.74 (m, 1H), 2.65-2.52 (m, 3H), 2.38-2.31 ( m, 2H), 1.96-1.88 (m, 1H) ¹³ C-NMR spectrum (trifluoroacetic acid-d, δ): 179.43, 175.63, 69.53, 34.92, 31, 75, 31.66, 27.63, 23.04. A sample for analysis was obtained by crystallization from water. Melting point: 277-280 ^o C (decomposition); [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = - 23 ^o (s = 1.35, 1H hydrochloric acid).

Example 17. 2-oxodicyclo [3.1.0] hexane-6-carboxylic acid
A mixture of 60 g of ethyl 2-oxodicyclo [3.1.0] hexane-6-carboxylate with 300 ml of 1N. The sodium hydroxide solution was stirred at 25-30 ^° C. After 2.5 hours, concentrated hydrochloric acid was added to adjust the pH to 0.8-1.2. The resulting solution was extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered and concentrated to obtain 49.1 g (98% yield) of crude material. As a result of recrystallization from 100 ml of ethyl acetate, the title compound of the example was obtained with a melting point of 123.5-128 ^° C.

Mass spectrum: m / z = 140 (M ⁺ ).

Elemental analysis data for C ₇ H ₈ O ₃ :
Calculated: C - 60.00, H - 5.75
Found: C - 60.14, H - 5.79
Example 18. - Salt of 2-oxodicyclo [3.1.0] hexane-6-carboxylic acid and (S) -1-phenylethylamine
A solution of 14 g of the compound obtained in Example 17 in 140 ml of a 25% solution of ethanol in ethyl acetate was combined with 1 equiv. (S) -1-phenylethylamine. After stirring overnight, the precipitated salt was isolated by filtration and dried to obtain 11.87 g (45.4%) of the target salt. The conversion of the salt, partially dissolved 2-oxodicyclo [3.1.0] hexane-6-carboxylic acid according to the method of example 17 and analysis showed that the enantiomeric excess for such a salt was 68%. This enantiomeric excess was determined by conversion to methyl ester with diazomethane followed by high pressure chiral liquid chromatography on a Chiralpak AS column at 40 ^° C, eluting with a mixture of 10% isopropanol with 90% hexane at a rate of 1 ml / min and detecting at a wavelength of 210 nm.

Example 19 - (+) - 2-oxodicyclo [3.1.0] hexane-6-carboxylic acid
A mixture of 1.31 g of the product of example 18 and 10 ml of 1N. hydrochloric acid was stirred for 5 min and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated to give 0.61 g of the title compound with a melting point of 110-115 ^° C. As determined by high pressure chiral liquid chromatography (as in Example 18, the enantiomeric excess for the product was 68%).

 Mass spectrum: m / z = 141 (M + H).

Optical rotation: α _D = 49.85 ^o
Example 20. - (-) - 2-Spiro-5'-hydantoindicyclo [3.1.0] hexane-6-carboxylic acid
Solution 1 eq. the compound obtained according to the above in example 19 (68% enantiomeric excess), 1.25 equiv. potassium cyanide and 2.5 equiv. ammonium carbonate was combined with each other and stirred at 25 ^o C in a mixture of ethanol with water for 40 hours. The mixture was acidified with 6n. hydrochloric acid, concentrated, diluted with water and filtered, obtaining a mixture of diastereomers in a ratio of 90: 10, the melting point of which was 286-290 ^o C, achieving 79% yield. This diastereomeric mixture was recrystallized from a mixture of isopropanol with water to give the compound indicated in the title of the example with a 48% yield, achieving 100% diastereomeric and 100% enantiomeric purity, the enantiomeric ratio was determined by high-pressure chiral liquid chromatography on a Chiracel column OD-H 4.6 x 150 mm in size, with a mixture of 15% isopropanol with 85% hexane at a flow rate of 1 ml / min at 40 ^° C and detecting at a wavelength of 220 nm, the diastereomeric ratio was determined by high-performance liquid chromatography pressure on a Zorbax SB-Phenyl column at 40 ^o C, eluting with a buffer mixture with acetonitrile in a ratio of 90:10, with a flow rate at elution of 2 ml / min and with detection at a wavelength of 220 nm (0.1 M solution of acid monohydrate was used as a buffer sodium phosphate, the pH of which was added to 2.1 by the addition of phosphoric acid).

Mass spectrum: m / z = 211 (M ⁺ H).

Optical rotation: α _D = -25.98
Elemental analysis data for C ₉ H ₁₀ N ₂ O ₄ :
Calculated: C - 51.43, H - 4.79, N - 13.33
Found: C - 51.38, H - 4.80, N - 13.26.

Example 21. - Ethyl 2-spiro-5'-hydantoindicyclo / 3.1.0 / -hexane-6-carboxylate
A mixture of 5.05 g of ethyl 2-oxodicyclo / 3.1.0 / hexane-6-carboxylate with 2.15 g of potassium cyanide, 5.77 g of ammonium carbonate, 30 ml of ethanol 2B-3 and 12 ml of water was stirred at 35 ^o C until completion of the reaction, as determined by high pressure liquid chromatography. After 15 hours, the reaction mixture was cooled to 0 ^° C. and 33 ml of water was added to the mixture. After 2 hours at 0 ^° C., the precipitate was isolated by filtration and dried, yielding 5.23 g (73% yield) of the title compound with a melting point of 217-220 ^° C.

 Mass spectrum: m / z = 238.1 (M +).

Elemental analysis data for C ₁₁ H ₁₄ N ₂ O ₄ :
Calculated: C - 55.46, H - 5.92, N - 11.76
Found: C - 55.74, H - 5.88, N - 11.50
Example 22. 2-Spiro-5'-hydantoindicyclo [3.1.0] hexane-6-carboxylic acid
A mixture of 16.32 g of the product of example 21 and 137 ml of 2n. The sodium hydroxide solution was stirred at 25 ^° C. After 1 hour, concentrated hydrochloric acid was added to adjust the pH to 1.0. The resulting precipitate was isolated by filtration and dried, yielding 13.70 g (95% yield) of the title compound with a melting point of 277-279 ^° C.

 Mass spectrum: m / z = 210.1 (M +).

Elemental analysis data for C ₉ H ₁₀ N ₂ O ₄ :
Calculated: C - 51.43, H - 4.79. N - 13.33
Found: C - 51.70, H - 4.93, N - 13.43
Example 23. (S) -1-Phenylethylamine salt of 2-spiro-5'-hydantoindicyclo [3.1.0] hexane-6-carboxylic acid
A mixture of 1.05 g of the product of example 22 with 16.6 ml of a solution of acetone in water in a ratio of 1.6: 1 was stirred at 25 ^o C, while adding 1.53 g of R - (+) - 1-phenylethylamine. This mixture was stirred for 2 hours at room temperature. The crystals were filtered off, washed with acetone and dried, yielding 0.74 g (45% yield) of the title compound at a temperature of 205-212 ^° C.

Optical rotation: α _D = -31.88 (c = 1, methanol).

Example 24.- (-) - 2-Spiro-5'-hydantoindicyclo [3.1.0] hexane-6-carboxylic acid
A mixture of 0.74 g of the product of example 23 with 10 ml of water was stirred at 25 ^° C., while the pH was adjusted from 6.81 to 1.0 by the addition of 1N. of hydrochloric acid. The reaction mixture was stirred for 1 h and the product was collected by filtration and dried, yielding 0.35 g (75% yield) of the title compound with a melting point of 310 ^° C. (decomposition).

 Mass spectrum: m / z = 210.1 (M +).

Optical rotation: α _D = -24.22 (c = 1, methanol).

Elemental analysis data for C ₉ H ₁₀ N ₂ O ₄ :
Calculated: C - 51.43, H - 4.80, N - 13.33
Found: C - 51.67, H - 4.87, N - 13.61
Example 25. - (+) - 2-aminodicyclo [3.1.0] hexane-2,6-carboxylic acid
A solution of 184 g of (-) - 2-spiro-5'-hydantoindicyclo [3.1.0] - hexane-6-carboxylic acid and 1750 ml of 3N. The sodium hydroxide solution was kept at the boiling temperature under reflux until the reaction was completed, as judged by high pressure liquid chromatography. After 28 hours, the solution was cooled to room temperature and filtered through glass fiber, removing trace amounts of insoluble material. By adding concentrated hydrochloric acid, the pH of the solution was adjusted to 3.0. The reaction mixture was stirred for 1 h at room temperature and two hours at 0 ^o C. The precipitated product was collected by filtration, washed with 170 ml of cold water and dried, obtaining 152.3 g (86% yield) of the title compound an example.

 Mass spectrum: m / z = 186.1 (M + 1).

Optical rotation: α _D = -23.18 ^o (c = 1, 1N hydrochloric acid).

Claims (10)

1. Derivatives of 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid of the formula I:

where X is (CH ₂ ) _n ;
R ² is CO ₂ R ⁴ and R ³ is hydrogen, or R ² is hydrogen and R ³ is CO ₂ R ⁴ ;
R ¹ and R ^{4 are} each independently hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, aryl or arylalkyl;
n is 1,
or pharmaceutically acceptable salts. 2. The compound according to claim 1, or its pharmaceutically acceptable salt, characterized in that it has a relative stereochemical configuration, as shown below

3. The compound according to claim 1 or 2, characterized in that R ¹ and R ⁴ each independently represent hydrogen, C ₁ -C ₄ -alkyl, aryl or arylalkyl, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 3, characterized in that R ¹ and R ⁴ each independently represent hydrogen or C ₁ -C ₄ -alkyl, or a pharmaceutically acceptable salt thereof. 5. The stereoomer according to claim 2, characterized in that it is (+) - 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid, its C ₁ -C ₄ alkyl, aryl or arylalkyl ether or a pharmaceutically acceptable salt. 6. The stereoomer according to claim 5, characterized in that it is (+) - 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid, its C ₁ -C ₄ alkyl ether or a pharmaceutically acceptable salt.  7. The stereoomer according to claim 6, characterized in that it is (+) - 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid or a pharmaceutically acceptable salt.  8. The stereoomer according to claim 7, characterized in that it is (+) - 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid.  9. A pharmaceutical composition exhibiting activity in the field of selective effects on negatively paired CAMP-linked metabotropic glutamate receptors, characterized in that it contains a pharmaceutically effective amount of the compound according to claim 1 in combination with one or more pharmaceutically acceptable carriers, diluents or excipients. 10. Derivatives of 2-spiro-5'-hydantoinbicyclo [3.1.0] hexane-6-carboxylic acid of the formula

where X is (CH ₂ ) _n ;
n is 1;
R ^2a is CO ₂ R ^4a and R ^3a is hydrogen, or R ^2a is hydrogen and R ^3a is CO ₂ R ^4a ;
R ^4a represents a carboxy-protecting group. 11. The compound of claim 10, wherein R ^4a is C ₁ -C ₆ alkyl.

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