Derivatives of 1,2,3,4-tetrahydro-2-naphtylamine

 

(57) Abstract:

The invention relates to new derivatives of 1,2,3,4-tetrahydro-2-naphtylamine, as well as their pharmaceutically acceptable salts, having the properties to affect 5-HTIAmammals and humans, as well as subclass of dopamine D2receptors, and may find application in the pharmaceutical industry. 22 C. p. F.-ly, 36 PL.

The invention relates to new derivatives of 1,2,3,4-tetrahydro-2-naphtylamine, with the properties to have interaction on 5-HTIAmammals and humans, as well as subclass of dopamine D2receptors, and may find application in the pharmaceutical industry.

Mental illnesses are considered to be disturbances in monoaminergic neural systems, particularly in systems containing serotonin (5-HT) and dopamine (DA).

Anxiety is associated with increased activity in 5-HT systems. In animals that had decreased levels of 5-HT, anti-fobia tests benzodiazepinovye Ancelotti, effective in all other cases, in this case, the activity did not show. Serotonin neurons are autoreceptor that when 5-HTIAagonists are anxiolytikum. Buspirone is selling 5-HTIAagonist with anxiolytic effects. Other 5-HTIAagonist is gepirone and it is clinically shown anti-fobia activity.

Depression is a psychological condition that is thought to be due to a decrease in the allocation of 5-HT. Many antidepressants stimulate the action of 5-HT by blocking the termination of its activity when re-injected into the nerve endings. 5-HTIAagonists are able to activate postsynaptic so that they can serve and antidepressants. For gepirone also shows the improving effects on individual symptoms in some depressed patients.

Serotonin is also involved in the regulation of feeding and sexual behavior and, in addition, in cardiovascular regulation. Thus, 5-HTIAagonists can be used in the treatment of obesity and sexual dysfunction. It is shown that these compounds change the power and sexual behavior of animals. The connection can also be used to treat obsessive-compulsive) violations of alcoholism and violent behavior. It is also known that 5-HTIAthe compounds can be used to treat hypertension, congestive heart failure (by reducing cardiovascular load) and heart attacks (by removing the sympathetic effects on the heart).

Schizophrenia, believed to be caused by overactive in DA systems. So, currently used protivoponosnye funds are DA antagonists. Dopamine autoreceptor suppress the degree of combustion DA neuron synthesis and its secretion. Therefore, it can be expected that agonists of autoreceptors may also be protivopekhotnymi means. In addition, DA agonists can be used to treat Parkinson's disease - disease caused by degeneration of DA neurons, and hyperprolactemia as DA agonists inhibit the secretion of prolactin.

Antagonists dopamine autoreceptors belong to a new class of drugs that increase the allocation YES due to the release of DA neurons under control of autoreceptors. Therefore, it can be expected that these drugs will be useful for treating conditions treatable by amphetamine and other stimulants, directly allocating YES. However agonists DA autoreceptors will be milder stimulants, because they do not produce directly the value of the cells under control of autoreceptors. Thus, it can be expected that antagonists of DA autoreceptors can be used to treat binge eating, disorders related to attention deficit, mental, cognitive and motor delays the mentally retarded and elderly patients, as well as for getting rid of nausea and dizziness when space travel.

Compounds of the invention have a variety of effects on 5-HTIAand YES-receptors, and therefore applicable in various fields associated with the manifestation of such activity.

Clinically, 5-HTIAagonists are also shown and anxiolytic properties. Such a remedy as buspirone is currently only selling 5-HTIA-agonist with anxiolytic activity. This compound exerts an antagonistic effect on dopamine receptors in the same dosage at which it stimulates 5-HTIA-receptors. Similar medication gepirone also has the properties of a dopamine antagonist. However, such properties antagonist of dopamine reduces the clinical applicability of these compounds as long-term treatment with antagonists of dopamine can lead to late dyskinesia.

Drugs, dashley nervous system, such as Parkinson's disease, schizophrenia and manicole-depressive state. In the case of Parkinson's disease, for example, neostriatal hypofunction can be restored by increasing stimulation of postsynaptic dopamine receptor. In the case of schizophrenia, the condition can be normalized by achieving a reduction of stimulation of postsynaptic dopamine receptor. The same effect can be achieved by inhibition vnutrennih presinapticheskih acts essential to establish adequate neurotransmission, transport and synthesis of the transmitter.

In recent years, a large array of pharmacological, biochemical and electrochemical data has developed a significant base in favor of the existence of specific populations of Central auto-regulatory dopamine receptors located in dopaminergically neuron. These receptors are part of a homeostatic mechanism that modulates the current of nerve impulses and synthesis of transmitter and regulating the amount of dopamine released from the nerve endings.

Direct agonists dopamine receptor, like apomorphine, is able to activate dopamine receptors, and tawadey of apomorphine in small doses, while when it is higher doses weakening the transmission of dopamine are outweighed by increased stimulation of the postsynaptic receptor. Protivorvotnoe and protivojishemicescoe the action of small doses of apomorphine is likely due to autoreceptor-stimulatory properties of this agonist dopamine receptor. The existing body of knowledge indicates that stimulants dopamine receptor with high selectivity to the Central nervous dopamine to autoreceptors would be very valuable in the treatment of mental disorders.

Known hydroxy-2-aminotetraline, in which the amine is substituted by one n-propylene, one benzyl or two n-cuts (see Arvidsson L. E., and others J. Med. Chem. 24, 921, 1981). Given a 5-, 6 - and 7-hydroxy as an active agonists Central dopamine receptors and 8-hydroxy as an agonist of the Central 5-HT-receptor lacking stimulating dopamine receptor activity.

Known 2-aminotetraline, in which the amino group is substituted by one or two metelli, atrami, n-propylene, isopropylene, n-butyl or benzilate (see Arvidsson L. E., and others J. Med. Chem. 27, 45, 1984). In addition, the above 2-piperidinylmethyl. Found, chii.

Described 8-hydroxy-1-methyl-2-(di-n-propylamino)tetraline, which are agonists of 6-HT receptors (see Arvidsson L. E., and others J. Med.chem. 30, 2105, 1987).

Also described 8-hydroxy - and 8-methoxytyramine derivatives (see Dervent 003891/47, 949981/51 and 0455351/48 (Arvidsson L. E., and others)).

Known 5,6-dihydroxy-2-aminotetralin (see Mc. Dermed, etc. J. Med. Chem. 18, 362, 1975) also described 5,6-dihydroxy-2-aminotetralin, 5,8-7,8-disubstituted derivatives. The amino group may be mono - or tizamidine simple alkyl group, benzyl or alkylacrylate or amino group may be represented by a 5 - or 6-membered hydrocarbon or heterocyclic amine. Indicated that these compounds have dofaminergicheskie properties, although it also indicates that some of these compounds are inactive.

Described 5-, 6 - or 7-hydroxy-2-dipropylenetriamine identified as dopaminergic compounds (Mc. Dermed, etc. J. Med. Chem. 19, 547, 1976).

Also described 5,8-disubstituted 2-aminotetraline, in which the amino group is not substituted or substituted by stands or lampropelma (see Rusterholz and other J. Med. Chem. 19, 99, 1976). Some of these compounds are inhibitors of prolactin are considered to be agonists of dopamine.

Lime-, n - or isopropoxy, or n-, sec - or tertbutoxycarbonyl, and the amino group not substituted or substituted by alkyl with 1 to 4 carbon atoms (see ATA and other J. Med. Chem. Soc. 2636, 1965). Indicated that the synthesized compounds for pharmacological testing. However, nothing is known about the use or pharmacological activity of the above-mentioned compounds.

Known 2-amino-1,2,3,4-tetrahydronaphthalene as selective inhibitors of re-assimilation (see Application EP 89304935.3).

Were also described 2-aminotetraline, in which the aromatic cycle substituted 5, 6, 7, or 8-position by a group R1where R1hydrogen, alkanoyl from 1 to 20 carbon atoms or the group-CO-(CH2)n-R7; n is 0 to 5; R7phenyl, substituted by various substituents; R2is hydrogen, hydroxyl, halogen or alkylsulfonamides; R3hydrogen; R4hydrogen, CH2OH, CH2-O=CO-R8or CH2-O-CO-(CH2)n-R followed razjasnenijami; R5and R6hydrogen, alkyl, or aryl or aralkyl, or R5and R6together represent alkylene with 4 to 6 carbon atoms (see the Federal Republic of Germany Patent DE 2803582). Indicated that the compounds have pharmacological activity, in particular stimulant, OK is soedineniya with a group R10in position and having a group R2or R4other than hydrogen.

Also described 2-aminotetraline, in which the aromatic cycle is not substituted or substituted 5, 6, 7, or 8-position by a group R1that represents methyl, and a saturated cycle is substituted by a group R2that represents alkyl with 1 to 6 carbon atoms, and an amino group substituted by a group R3that represents hydrogen or alkyl with 1 to 6 carbon atoms (see Patent UK 1377356). It is reported that these compounds possess analgesic activity. As an example, the compounds mentioned 1,1-dimethyl-2-(N, N-dimethylamino)-7-hydroxytyramine. The same compounds listed in Chem. Abstr, 79, 146294 like compounds with analgesic and accelerating bowel action.

Described 1-methyl-2-(cyclopropylamino)-5-methoxytyramine and indicate that the connection has local anaesthetic activity (see J. Pharm. Sci. 67, 880-82, 1976)

Publication in Derwent 58247B/32, 40378A/23, 83-729388/32, 83-72987/32, 29348/17 and 06733/05 are carboxyterminal. Additional document 07833/05 refers to 8-amido - 8-alkylaminocarbonyl.

In the patent application EP 270947 (1988) revealed 8-hydroxy and 8-methoxytyramine.

In the patent application EP 272534 (1988) rescrit. Hjorth S. Carlsson A. Lindberg P. D. Sanches Wikstron H. Arvidsson L. E. Hacksell V. Nilsson, J. L. G. J. Neural Transm. 1982, 55, S. 69; Mellin C. Bjork L. Karlen A. Johansson, A. M. S. Sundell Kenne L. Nelson D. L. Anden H. E. Hacksell V. J. Med. Chem. 1988, 31, 1130 S.; Cossery J. M. Gozlan H. Sapampinato V. Perdicakis C. Guillaument G. L. Pichat Yamon M. Eiropean J. Pharmacol, 1987, S. 140 143).

The purpose of the invention is to provide compounds for use in medicine, particularly compounds with therapeutic activity against Central nervous system. Another objective of the invention is to provide compounds that affect 5-HTIA-receptors in mammals, including humans. And another objective of the invention is to provide compounds that affect the subclass of dopamine receptors, known as the D2-receptors.

Methods of obtaining these compounds, and their pharmaceutical use and pharmaceutical preparations using such compounds constitute additional aspects of the invention.

According to the invention offers derivatives of 1,2,3,4-tetrahydro-2-naphthylamines General formula I

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where R is hydrogen or OCH3;

R1represents: (a) hydrogen, b) -OH, c) -O(C1-C4)alkyl, (o) -CONR7R8e) -het, f) -C(O)het, g) -CF3h) -SO2NH
R2represents: (a) hydrogen, b) -(C1-C8)alkyl, c) -(C3-C5)alkenyl, d) -(C3-C8)quinil, e) -(CH2)m-(C3-C8)cycloalkyl, f) -(CH2)m-aryl, (g) -trimethylsilylmethyl, h) -(CH2)m-CO2R6and C(O)CH3;

R3accepts values of R2(a h) or (i) (CH2)m-indole, substituted C1-C4alkoxyl, j) (CH2)m-6-phenyl-4H-5-triazolo[4,3-a][1,4]benzodiazepine-1,6-phenyl substituted in the aromatic ring by halogen, k) [(2,3-dihydro-1,1-dioxo-3 - oxibendazole)-(CH2)n]- i) 1,3-benzodioxolyl-(CH2)n-, m) R2and R3together with the nitrogen atom form

R4represents: (a) hydrogen, b) -(C1-C8)alkyl, c) -(C2-C8)alkylen, d) -(CH2)m-(C3-C8)cycloalkyl, e) -(CH2)m-CO2R6f) methylene;

R5hydrogen or -(C2-C8)-alkenyl;

where R6R7and R8independent means: a) hydrogen, b) -(C1-C4)alkyl, c) -(C1-C4)alkaryl;

where X is: (a) -(CR6R6)n-, b) -(CR6R6)n-O-(CR6R6)q-, c) -(CR6R6)n-S-(CR6R61is hydroxyl or metaxylem, R4and both R2and R3cannot be hydrogen, alkyl or cyclopropylmethyl, R2and R3taken together with the nitrogen atom, may not be the piperidine; that, when R1alpha-CONH2, R2and R3both can not be cut; when R1, R4and R5are hydrogen, or R2or R3are hydrogen, the other cannot be ethylene.

Preferred are the compounds of formula I, selected from the following group: 8-(oxazol-5-yl)-1,2,3,4-tetrahydro-2-N, N-di-n-propylaminoethyl or its hydrochloride; 8-(3-bromination-5-yl)-1,2,3,4-tetrahydro-2-N, N-di-n-propylaminoethyl or its hydrochloride.

Particularly preferred compounds I where R1-CO-NR7R8in particular compounds, where the group-CONR7R8is N-alkylaminocarbonyl.

Such compounds are compounds selected from the group comprising 1,2,3,4-tetrahydro-2-N, N-di-n-propylaminoethyl-8-yl-N - benzylcarbamoyl or its salt with maleic acid; 1,2,3,4-tetrahydro-2,N,N - dicyclopentadienyl-8-yl-N-methylcarbamate; 1,2,3,4-tetrahydro-2-N - cyclopropylmethanol-8-yl-N-metelka is ini connections, I, where R1-(CO)-het, in particular (1,2,3,4-tetrahydro-2-N, N - dicyclopentadienyl-8-yl)(2-pyrrolyl)ketone.

Preferred compounds I where R2and R3together with the nitrogen atoms to which they are attached, form a loop

In particular, these compounds are selected from the group consisting of CIS-2,6-dimethyl-4-(1,2,3,4-tetrahydro-8 - methoxy-2-naphthalenyl)morpholine; TRANS-2,6-dimethyl-4-(1,2,3,4-tetrahydro-8 - methoxy-2-naphthalenyl)morpholine; 4-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)thiomorpholine or its hydrochloride; 7-[hexahydro-1(2H)-azocine] -1-methoxy-5,6,7,8-tetrahydronaphthalen or its hydrochloride; 7-[hexahydro-1(2H)-azocine] -5,6,7,8-tetrahydro-1-naphthalenol or its hydrochloride; 2-(1-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalen or its hydrochloride.

For the preferred group includes the compounds where R4selected from the group including C1-C8-alkyl, C3-C8alkenyl, -(CH2)m-C3-C8-cycloalkyl,

-(CH2)m-CO2R6and -(CH2)m-OR6where R6takes the values specified above.

These compounds include compounds selected from the following group: TRANS-1,2,3,4-tetrahydro-8-methoxy-1-(2 - propenyl)-N-propyl-2-chlorid; CIS-1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N-propyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N, 1-dipropyl-2-naphthylamine or hydrochloride; CIS-1,2,3,4-tetrahydro-8-hydroxy-N, 1-dipropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-hydroxy-N,N,1-tripropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N,N,1-tripropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N, 1-di-2-propenyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-N, 1-di-2-propenyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-1 - cyclopropylmethyl-N-propyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-N,1-bis-cyclopropylmethyl-2-naphtylamine or hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-1-(2 - propenyl)-N-cyclopropylmethyl-2-naphtylamine or hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N, 1-bis-cyclopropylmethyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N-cyclopropylmethyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-1-(2-propenyl)-N-propyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-1-(2-propenyl)-N-propyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-5-methoxy-1-(2-propenyl)-N-PR is hydrochloride; CIS-1,2,3,4-tetrahydro-1-hydroxymethyl-8 - methoxy-N-propyl-2-naphtylamine or its hydrochloride; CIS-1-(cyclopropylmethyl)-1,2,3,4-tetrahydro-8 - methoxy-N-2-propenyl-2-naphtylamine or its hydrochloride; TRANS-1-(cyclopropylmethyl)-1,2,3,4-tetrahydro-8-methoxy-N-2-propenyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-1 - hydroxymethyl-N-2-propenyl-2-naphtylamine, or its hydrochloride, TRANS-1,2,3,4-tetrahydro-8-methoxy-1-hydroxymethyl-N-2-propenyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-hydro-N, 1-di-(2-propenyl)-2-naphtylamine or its hydrochloride.

You should also highlight the compounds I where R1a methoxy group, R5C2-C8alkenyl, and R2and R3take the value specified above.

These include, in particular, include compounds selected from the group comprising CIS-1,2,3,4-tetrahydro-8-methoxy-N, 3-dipropyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-metoki-N,3-dipropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-3-propenyl-N-n-propyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-3-propenyl-N-n-propyl-2-naphtylamine or its hydrochloride.

Preferred are the compounds of formula I, where R2and R3Odin is l, and R1takes the values specified above, provided that when one of R2or R3hydrogen, then the other cannot be 1-propanolol.

In particular, it relates to compounds selected from the group comprising 1,2,3,4-tetrahydro-8-methoxy-N,N-di-2-PROPYNYL-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-2-PROPYNYL-2-naphtylamine,

1,2,3,4-tetrahydro-8-methoxy-N-2-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N, N-di-2-propenyl-2-naphtylamine or its hydrochloride; N-ethyl-1,2,3,4-tetrahydro-8-methoxy-N-(2-methyl-2-propenyl)-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-2-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-(2-methyl-2-propenyl)-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-N-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-methyl-N-2-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-methyl-N-(2-methyl-2-propenyl)-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-N-2-PROPYNYL-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-hydroxy-N, N-di-2-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-methyl-N-2-PROPYNYL-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-N, N-di-2-prop the hydrochloride; TRANS-1,2,3,4-tetrahydro-N,1-di-2-propenyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N-methyl-1 - hydroxymethyl-N-n-propyl-2-naphtylamine or its hydrochloride; N-(cyclopropylmethyl)-1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine or its hydrochloride; N-(cyclopropylmethyl)-1,2,3,4-tetrahydro-2-naphtylamine or its hydrochloride; N-(cyclopropylmethyl)-1,2,3,4-tetrahydro-8-hydroxy-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-N-methyl-N-n-propyl-2-naphtylamine or its hydrochloride.

As well as to compounds selected from the group comprising 1,2,3,4-tetrahydro-N-2-propenyl-2-naphtylamine, or its hydrochloride, or compounds selected from the group comprising 1,2,3,4-tetrahydro-8-methoxy-N-methyl-N-2-propenyl-2-naphtylamine and its hydrochloride or 1,2,3,4-tetrahydro-8-methoxy-N-2-PROPYNYL-2-naphtylamine.

Of the compounds of formula I it is necessary to provide compounds of formula I

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where R1, R2, R3and R4have the values specified above.

In particular, it relates to compounds from the group comprising 1,2,3,4-tetrahydro-1-methenyl-8-methoxy-N-(2 - propenyl)-N-n-propyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-1-methenyl-8-methoxy-N-methyl-N-n-propyl-2-naphtylamine or its hydrochloride.

To UB>2and 5-oxazolyl, and R2and R3may be the same or different and are selected from the group including hydrogen, C1-C8-alkyl.

Particularly preferred compounds of formula I are compounds from the group comprising (+)-8-trifluoromethyl-2-N-n-propylaminoethyl; (-)-8-trifluoromethyl-2-N-n-propylaminoethyl; (+)-8-trifluoromethyl-2-N,N-di-n-propylaminoethyl; (-)-8-trifluoromethyl-2-N, N-di-n-propylaminoethyl; 8-bromo-2-N, N-di-n-propylaminoethyl, 8-formyl-2-N,N-di-n-propylaminoethyl; 8-(5-oxazolyl)-2-N,N-di-n-propylaminoethyl; 8-aminosulfonyl-2-N-n-propylaminoethyl; 8-aminosulfonyl-2-(N-allylamino)tetralin; 8-aminosulfonyl-2-(N,N-dipropylamino)tetralin; 8-aminosulfonyl-2-(N-(3-fenoprofen)amino)tetralin.

Individual compounds of the invention have selective pharmacological properties and are applicable for the treatment of disorders of the Central nervous system, including symptoms of depression, symptoms of psychosis, anxiolytic symptoms: panic attacks, obsessive-compulsive disorders, senile dementia, emotional disturbances associated with dementia, as well as to stimulate sexual activity. Individual compounds of the invention are also applying. Individual compounds of the invention, also applicable as anti-diabetic, protivogipertonicheskoe funds and anti-obesity and to treat sexual impotence.

Compounds of the invention are identified in two ways: by chemical name and reference to the structural formula shown on the appropriate diagram. In necessary cases, the scheme is also specified and the appropriate stereochemistry.

A variety of carbon fragments are defined as follows.

Alkyl refers to an aliphatic hydrocarbon radical of normal or ISO-structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and n-octyl.

Alkoxygroup presented in the form OR1where R1- C1-C8refers to the alkyl radical attached to the remainder of the oxygen molecule, and includes branched or unbranched forms such as methoxy, ethoxy-, n-propoxy, isopropoxy, h-butoxy, isobutoxy-, second -, butoxy-, tert-butoxy, h-pentox, isopentane, neopentane, h-hexose, isohexane-.

Alkenyl twinnie, and unbranched forms such as ethynyl-, 1-methyl-1-ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 1 pentyl, allyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 4-hexenyl, 1-methyl-4-hexenyl, 3-methyl-1-hexenyl, 3-methyl-1-hexenyl, 3-methyl-2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-methyl-1-heptenyl, 3-methyl, 2-heptenyl, 1-octenyl, 2-octenyl or 3-octenyl.

Cycloalkyl refers to the radical of saturated cyclic hydrocarbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Gets refers to a heterocycle with five atoms containing nitrogen, carbon, and in some cases oxygen, including 2-pyrrolyl, 2-oxazolyl, 2-imidazolyl, 2-oxazolyl, 2-imidazolyl.

Halogen refers to bromine, chlorine or fluorine.

6-phenyl-4H-5-triazolo[4,3-a] [1,4] benzodiazepine refers to the remains of benzodiazepines (see U.S. Patent 3987052), including residues such famous CHC connections as alprazol and triazole.

For professionals it is obvious that the compounds of the invention should have chiral centers. Scope of the invention includes all enantiomeric or diastereomeric form compounds formylmethionine carbon atom in the fragment of a busy cycle, including the carbon atoms of the loop adjacent to the nitrogen atoms. therapeutic properties of the compounds may be more or less dependent on the stereochemistry of a particular connection. Pure enantiomers, such as enantiomeric or diastereomeric mixture, covered by the scope of the invention.

For the formation of a non-toxic pharmaceutically acceptable salts of the compounds of the invention with acids can be used both organic and inorganic acids. For illustrations such acids as sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmitic, ethicality, sulfamic, amber, cyclohexylsulfamate, fumaric, maleic and benzoic acid. These salts can easily get by known methods.

Compounds of the invention can be obtained by one of the methods described below and reflected on the above charts.

Compounds of the invention in which R1alkylamino or dialkylamino, and R2and R3hydrogen or alkyl, can be synthesized by the method illustrated by scheme A.

In stage 1 scheme And substituted 2-tetralone And 1 treated with ethylene glycol in the presence of n-taleem a-2. Source substituted tetralone, for example 8-methoxytyramine, readily available or can be obtained by known methods.

In stage 2 compound a-2 is transformed into the corresponding hydroxy-3 by boiling the reaction mixture of diphenylphosphine and n-utillity.

In stage 3, the compound a-3 is introduced into the reaction with the anhydride triftormetilfullerenov acid in the presence of methylene chloride and pyridine to obtain tetraline a-4.

In stage 4 through a mixture of compounds a-4, palladium acetate, bis(diphenylphosphino)propane, diisopropylethylamine, methanol and dimethyl sulfoxide miss monoxide and receive connection A-5.

At stage 5, the compound a-5 hydrolyzing in the presence of a base such as potassium hydroxide, to obtain the compound A-6.

On stage 6 connection A-6 and carbonyldiimidazole dissolved in a solvent such as THF and the resulting solution is injected into the reaction with a saturated solution of ammonia in THF with the formation of compound a-7.

On stage 7, the compound a-7 is dissolved in a solvent such as acetic acid, and by heating get the connection a-8.

In phase 8, the compound a-8 enter into reaction with suitable is underwater A-9.

On stage 9 boiling compounds A-9 with h-haloalkane in the presence of sodium carbonate and acetonitrile get 2-N, N-dialkylaminoazodyes A-10.

In addition, compound A-5 (B-1) can be converted into compounds of formula I, where R1arylcarbamoyl, the method illustrated by scheme B.

In stage 1 a solution of compound B-1 (A-5) is injected into the reaction with the adduct of pyrrole in the presence of ethylmagnesium getting connection B-2.

In stage 2 conduct the reaction of the compound (B-2 N-alkylamines in the presence of acetic acid, platinum oxide and absolute ethanol in an atmosphere of hydrogen and receive N-alkylamidopropylamine B-3.

At stage 3 N,N-dialkyldithiophosphate B-4 is produced by reaction of the compound (B-3 with n-haloalkane in the presence of a base such as sodium carbonate and a solvent such as acetonitrile.

Methods for obtaining compounds of the formula I, in which R1represents hydrogen, OR6or SR6are reflected by the methods illustrated in schemes C K. In each of these ways as a source products use derivatives of 2-tetralone.

Scheme C.

In stage 1 substituted 2-tetralone C-1, where R1, R2and R3have SS="ptx2">

In stage 1 substituted 2-tetralone D-1 by reductive amination in turn substituted aminotetralin D-2. In stage 2 compound D-2 transform 2-aminotetralin D-3, which is at stage 3 by reductive amination converted into N-substituted aminotetralin D-4.

Diagram E.

In stage 1 substituted 2-tetralone E-1 alkylate 2-position by alkylhalides in the presence of a base according to well known methods of alkylation with obtaining compound E-2. At the stage 2 compound (E-2) is subjected to reductive aminating and get the compound E-3.

Diagram F.

In stage 1 substituted tetralone F-1 is introduced into the reaction dimethylcarbonate in the presence of a base, such as LDA, to obtain the compound F-2. In stage 2 the reaction of the compound F-2 alkylhalides in the presence of a base to receive the compound F-3. At stage 3 the decarboxylation of compound F-3 to obtain compound F-4. In stage 4 the compound F-4 is subjected to reductive aminating and receive connection F-5.

Connection G.

In stage 1 substituted tetralone G-1 (F-2) by known methods is subjected to reductive aminating. Compound G-2 by reaction with propionic anhydride in pyrid compound G-4. Compound G-4 stage 4 totalrevenues with subsequent elimination in the presence of reasonable grounds make known methods in the compound G-5.

According to scheme H, based on 2-bromophenylacetonitrile, are optically active 8-trifluoromethyl-2-N-[(R)-alpha-methylbenzyl]-2-N-propylaminoethyl H-8, which is then converted into the corresponding compound H-10.

Scheme I shows the receipt of 8-(5-oxazolyl)-2-di-n-propylaminoethyl I-4, from 8-bromo-2-tetralone.

In scheme J illustrates the possibility of obtaining 8-aminosulfonyl-2-tetralone, on the basis of 8-bromo-2-(Spiro - 1,3-dioxolane-2-yl)tetralin.

In scheme K retrieves 8 diamido-2-di-n-propylaminoethyl.

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How restorative amination well known in the above methods may be used any of the following ways. One such method involves the reaction of tetralone with an amine in the presence of cyanoborohydride sodium and glacial acetic acid in a mixture of tetrahydrofuran-methanol.

8-Aminopropane A-10 can be converted into the corresponding 8-cyanoderivatives the reaction of the compound with a salt of Burgess(see Organic Synthesis, 56, S. 40).

In the clinic compounds of the invention typically can be administered orally, rectally or by injection in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic salts with an acid, such as hydrochloride, lactate, acetate, sulpham, in a mixture with a pharmaceutically acceptable carrier. The use and introduction of drugs to the patient being treated in the clinic, it is obvious to an ordinary person skilled in the field.

Medicinally acceptable daily dosage of the compounds of the invention are 1 to 2000 mg, for oral administration, preferably 50 to 500 mg, and 0.1 to 100 mg for parenteral administration, preferably 0.5 to 50 mg.

Compounds of the invention in which R1is 8-position in the aromatic cycle, are highly selective agonists of 5-HTIA-receptor with minor dopaminergic activity or its absence. The ratio IR50dopamine D2to 5-HTIAfor data binding, in vitro and shown in table. 1, for one of the compounds of the invention shows selectivity for 5-HTIAthe recipe is Noah duration of action. Both of these elements are useful for effective clinical treatment.

The possibility of using compounds of the invention for the treatment of disorders of the Central nervous system are shown in behavioral, physiological and biochemical tests, methods of which are described below.

The binding. Inhibition of binding of 8-OH-DPAT in the homogenate of bovine brain. Potency is given in the dosage (nm) required for inhibition of 50 DPAT binding (IR50). This test measures the ability of binding with 5-hydroxytryptamine (5-HTIA) receptor.

Hypothermia. Four mice subcutaneously injection the test compound, starting with a dosage of 30 mg/kg After 20 min count the number of animals, the temperature of the bodies which fell by 2oC or below. If all four mouse reaches the specified criterion, in this case, the drug is considered active and the subsequent readings removed after 60 and 120 min after drug administration. The minutes indicate the time for the last statistically significant impact of drugs on the average body temperature. For all active connections dosage reducing with an interval of 0.5 log until until you find the dose, not decreasing temperature pH temperature drop two out of four mice) and calculate according to the statistics of Spearman-Carbera.

The discharge of the sympathetic nerve (RSN). Identify input (centuries ) dose (mg/kg), causing a reduction of 50 DCL shot at chloralose cats, as well as the maximum inhibition of sympathetic activity observed in the tested interval dosing (0,002 1 mg/kg centuries).

CD RSN/MAX. Blood pressure had shot chloralose cats in percent of control at dose levels causing a decrease DCL 50 and maximum reduction in blood pressure as a percentage of control for the same cats observed in the range of concentrations (0.001 to 1 mg/kg centuries).

Biological data for the Central nervous system and protivogipertonicheskoe biological data are given respectively in table. 1 and 2.

Compounds of the invention are applicable as antidiabetics and anti-obesity. Though all connections have all the specified pharmacological activity, however, the applicability of specific compounds can be determined by a specialist using the following tests.

1. Antidiabetic.

A. Testing for lowering blood glucose in ADCYthe mice.

All used ADCYmice receive and are selected by well-known methods (see T. Fujita is a, carried out by previously described methods, collect samples nesasanai blood glucose (NSGC) for untreated mice. The values obtained in blood sugar used for placing animals in groups with equal average concentrations of sugar in the blood and to eliminate mice with a value NSGC < 250 mg/DL. On the eve of the selected test compound is injected into the ground to eat the mice (Purina 5015). The compound is administered at a dose of 1 mg/g of food. Typically, for each group prepare 300 g containing the medicine of food. Mice receiving only grind the food, serve as a negative control.

In each series of selection also use ciglitazone (see T. Fujita, etc. see above) as a positive control (0.5 to 1 mg/g) of food.

On the first day to determine the initial body weight and food. Food is placed in the trough in sufficient quantity for the entire period of testing. In order to accustom accustomed to granulated food mice to grind food, mice fed ground food for nine days before their selection. On the fourth day of testing newly selected samples NSGC, and again determine the body weight and food. Determine food consumption conducted to determine the average dose (mg/g), Eligibility and activity of compounds determine based on the following criteria.

A. Negative control.

This group should not show significant changes (p < 0,05) before and after treatment. If there is a significant lowering of blood sugar experience is considered invalid.

B. a Positive result.

This group should show a significant decrease in average glucose values in the blood before and after treatment. The lack of activity in this group also leads to the recognition of the experience of the void.

C. Negative control in comparison with the positive control.

The comparison must give significant results. This is an additional guarantee that both control groups behave as expected.

Was The Connection.

The activity of compounds is determined by several criteria:

1) a significant decrease of average values of blood sugar before and after treatment;

2) negative control in comparison with the positive control.

The identified difference allows to determine the difference between groups that need to be considered as the connection is active.

II. Activity against coolant is ad Libitum. Daily determine food consumption. Animals orally administered compound in tween 80 at a dose of 100 mg/kg or 200 mg/kg Control receives an equivalent amount of (0,25) tween 80. If the daily consumption of food treated rats is lower than the control, within 4 g, in this case, consider that the connection has anorexically activity.

The experimental method.

Using the above methodology, it is possible to implement the invention in full. The following detailed examples illustrate how to obtain the various compounds and/or perform the various processes of the invention, and these examples should be considered as merely illustrative and in no way limiting the preceding description. For the specialist would not be difficult to identify possible variations of the above methods both in terms of reagents and conditions, and technology.

Preparative example 1. 8-Methoxy-2-[Spiro-2-(1,3-dioxole)tetralin] (a-2, scheme a).

In a round bottom flask is charged with 8-methoxy-2-tetralone (50 g, 284 mol), ethylene glycol (35.2 g, 2 equiv.) p-toluensulfonate (80 mg) and benzene (600 ml). The solution is boiled for 7 hours with removal of water formed in the trap Dean-stark. Then rostrally. The organic layer was washed with water (300 ml) and brine (300 ml). Water layers again extracted with ether (500 ml). The organic layers are combined and dried over anhydrous sodium sulfate and after removal of the solvent in vacuo obtain 56 g of the title compound (yield 96).

Preparative example 2. 8-Hydroxy-2-[Spiro-2-(1,3-dioxolan)]tetralin (a-3, scheme a).

To a cooled to 0oC solution diphenylphosphine (30,65 ml, 176 mmol) in THF (300 ml) is added n-utility (170 mmol). The resulting anion red is stirred for 30 minutes, then add 8-methoxy-2-[Spiro-2-(1,3-dioxolan)]tetralin (25 g, 113,6 mmol) in THF (100 ml). The solution is boiled for 24 h, then cooled in a bath with ice and add saturated aqueous solution of ammonium chloride. Then add ether (800 ml) and the extraction is carried out. The organic layer was washed with saturated aqueous sodium bicarbonate (200 ml), then brine and dried over anhydrous sodium sulfate. The solvent is removed in vacuum, the residue is placed in a chromatographic column with silica gel (6 cm x 40 cm) and elute with a mixture of ethyl acetate-hexane (5 to 95, with the transition 30 70 for elution of the product). Removal of solvent in vacuo gain of 21.2 g of a white solid substance (102,9 mmol, yield 90).

Preparative example 4. 8 Carbomethoxy-2-[Spiro-2-(1,3-dixylyl)]tetralin (A-5, scheme a).

In a round bottom flask is charged with 8-trifloromethyl-2-[Spiro-2-(1,3-dioxolan)] tetralin (62 g, 186,4 mmol), palladium acetate (2,88 g, 7 mmol), bis(diphenylphosphino)propane (for 6.81 g, 9 mmol), Diisopropylamine (70,3 ml, 2.2 equiv.) methanol (183 ml) and dimethylsulfoxide (550 ml). The flask was thoroughly rinsed with carbon monoxide, which is then passed through the solution. The solution is heated to 70oC and stirred for 4 h Then the solution is cooled wodnym sodium sulfate. Removal of solvent in vacuo, filtered through a layer of chromatographic silica gel (6 cm x 30 cm) with a mixture of ethyl acetate-hexane (25 75) with the subsequent removal of solvent to obtain 39 g (yield 85) of the title compound in the form of butter.

Preparative example 5. 1,2,3,4-Tetrahydrofuro[-2(1,3-dioxolane)-2-naphthalene]-8-yl-carboxylic acid (A-6, scheme 6).

In a mixture of water (50 ml) and methanol (150 ml) was dissolved methyl ester of 1,2,3,4-tetrahydrofuro[2-(1,3-dioxolane)-2-naphthalene] -8-yl-carboxylic acid (25 g, 101 mmol) and potassium hydroxide (28,2 g, 5 EQ.) and the solution is boiled for 2 hours and Then the solution is cooled and most of the solvent is removed in vacuum. The residue is dissolved in water (300 ml) and extracted with ether (2 x 200 ml). The aqueous solution is cooled in a bath of ice and acidified with concentrated hydrochloric acid to pH 2. An aqueous solution quickly extracted with ether (2 600 ml), organic layers combined, washed with brine (2 x 300 ml), dried over anhydrous sodium sulfate and after removal of the solvent in vacuo gain of 21.5 g (yield 91) carboxylic acid in the form of a white substance so pl. 142oC.

Preparative example 6. 1,2,3,4-Tetrahydrofuro[2-(1,3-dioxolane)-2-naphthalene-8-yl]carboxamide (a-7, scheme a).

100 ml of Intimidator (11 g, 1.2 EQ.) and stirred for 6 h, then cooled to 0oC add a solution of THF (40 ml), saturated at 0oC ammonia. The reaction mixture is close to retain ammonia, heated to 25oC and stirred for 5 hours Then add methylene chloride (200 ml) and ether (200 ml), the solution is transferred into water (500 ml) and extracted. The organic layer was washed with 2 N. hydrochloric acid (300 ml), water (300 ml), saturated aqueous sodium bicarbonate (300 ml), brine (300 ml) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo get 7,88 g (yield 60) of the title compound as a white solid.

Using the method similar to preparative example 6, but replacing ammonia appropriate amine, to obtain the corresponding N-alkylcarboxylic of aminotetraline.

Preparative example 7. 1,2,3,4-Tetrahydro-2-oxidation-8-yl-carboxamide (a-8, scheme a).

In a mixture of acetic acid-THF-water (3 1 1) dissolved 1,2,3,4-tetrahydrofuro[2-(1,3-dioxolane)-2-naphthalene]-8-yl-carboxamide (7,88 g, 33.8 mmol) and heated 5 h at 60oC. Then the solution is cooled and removal of solvent in vacuo get white substance by recrystallization from 95 ethanol-hexane poluchili-8-yl)(2-pyrrolyl)ketone (- 2, the schema).

In 40 ml of toluene is dissolved pyrrole (3,17 ml) and cooled to 0oC with the addition of ethylmagnesium (15.2 ml) and 3 M solution in ether). The resulting solution was left to warm to 25oC m stirred for 30 minutes Then add a solution of methyl ester of 1,2,3,4-tetrahydropyran-2-[2-(1,3-DIOXOLANYL)]naphthalene-8-yl-carboxylate (5,15 g of 20.8 mmol) in toluene (200 ml) and the resulting solution is boiled for 24 hours and Then the solution is cooled and neutralized by adding saturated aqueous solution of ammonium chloride. After adding ether (100 ml), the solution is extracted. The organic layer was washed with water (2 x 100 ml), saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml). Dried over anhydrous sodium sulfate and removal of solvent in vacuo get a dark oil, which is transferred into a mixture of acetic acid-THF-water (3 1 1) and heated 5 h at 50oC. After cooling, the solvent is removed in vacuum and the residue is transferred into a chromatographic column filled with silica gel (3 cm x 40 cm) and elute the mixture of ethyl acetate-hexane (40 60) (add methylene chloride to remove columns crystalline product). Removal of solvent obtain 3.7 g (yield 74 title compound in the form of light yellow needles (so pl. 174othe Rina sodium (20 g), 1-chloro-4-bromobutane (16,8 ml) and DMF (150 ml) is stirred for 15 h at 90oC. Then the solution is cooled and added ether (200 ml) and water (400 ml of the resulting mixture was extracted and the organic layer washed with water (4 x 300 ml) and brine (100 ml). The organic layer is dried over anhydrous sodium sulfate and the solvent is removed in vacuum. The residue is transferred into a chromatographic column filled with silica gel and elute with a mixture of ethyl acetate-hexane (20 to 80). Removal of solvent in vacuo receive oil (24.5 g). The oil is dissolved in acetone, to the solution was added sodium iodide (2 EQ. ) and boiled for 6 hours After filtration and removal of solvent in vacuo, the residue is filtered through a layer of chromatographic silica gel with a mixture of ethyl acetate-hexane (30 70). Removal of solvent receive oil that solidified upon standing.

Preparative example 10. 3-Iodine-N-propyl-(2,3-dihydro-1,1-dioxo-3-benzisothiazol) and 5-iodine-N-pentyl-(2,3-dihydro-1,1-dioxo-3-benzisothiazol) synthesized by the method similar to the method of preparative example 9.

1-Phenyl-2-imidazolidone, 1-(3-chlorophenyl)-2-imidazoline and 1-(2-methoxyphenyl)-2-imidazolidone obtained according to a known method (see W. B. Wright Jr. H. J. Bradander, P. A. Hardy, Jr. A. C. Osterberg, J. Med. Chem. 9, 852, 1966).

The drug is an der, P. A. Harday Jr. A. C. Octerberg, J. Med. Chem. 9, 852, 1966) (3,24 g, 0.02 mol), 1-bromo-4-chlorobutane (10,29 g, 0.06 mol) tetrabutylammonium (0.64 g, 2 mmol) and 50-Noah aqueous sodium hydroxide (60 ml) in toluene (100 ml) was intensively stirred for 9 h at an oil bath at 60oC and about a day at room temperature. The mixture is then diluted with water and diethyl ether and the layers separated. The aqueous layer was extracted with diethyl ether, the combined organic layers washed with brine and dried (MgSO4). Removal of solvent in vacuo receive oil (9.2 grams). Cleaning pressure chromatography (SiO2, 230 400 mesh. hexane-ethyl acetate 3 1) receive a colorless solid (4.83 g), recrystallization of a sample (0.5 g) from a mixture of diethyl ether-hexane obtain colorless crystals of the title compound (0,489 g) so pl. 47,5oC.

Preparative example 12. 1-Phenyl-(4-edbutil)-2-imidazolidone.

A mixture of 1-phenyl-(4-chlorobutyl)-2-imidazolidone (1,87 g, 7.4 mmol) and sodium iodide (of 5.55 g, 37 mmol) in acetone (60 ml) is boiled with stirring for 16 hours the mixture is Then diluted with diethyl ether, filtered, evaporated to dryness. The residue is partitioned between diethyl ether and water and the aqueous layer was extracted with methylene chloride. United organic the e compound as a yellow solid (2.28 g, 90).

Similarly synthesized 1-phenyl-(3-improper)-2-imidazolidone, 1-(3-chlorophenyl)-(4-edbutil)-2-imidazolidone, 1-(3-chlorophenyl)-(3-improper)-2-imidazolidone, 1-(2-methoxyphenyl)-(4-edbutil)-2-imidazolidone, 2,4-dihydro-2-(4-edbutil)-1H-[1,2,4] triazolo[3,4-C][1,4]benzoxazin-1-he and 2,4-dihydro-2-(3-edbutil)-1H-[1,2,4]triazolo[3,4-C][1,5]benzoxazin-1-it.

Preparative example 13. 1,2,3,4-Tetrahydro-2-oxo-(2-propenyl)naphthalene (E-2, scheme E) and 1,2,3,4-tetrahydro-2-oxo-1,1-di(2-propenyl)naphthalene.

To a solution of 7.3 g (50 mmol) of 2-tetralone in 75 ml of THF in a three-neck flask, equipped with input for gas and tube, in a nitrogen atmosphere at -30oC add to 36.7 ml of LDA (55 mmol, 1.5 M in cyclohexane). The solution is allowed to warm to 0oC for 30 min, then was added 5.6 ml (65 mmol) of allylbromide. The progress of the reaction is controlled by TLC. After stirring 24 h at room temperature the reaction mixture is neutralized 10% sodium bisulfate to pH 2-3. After removal of THF under reduced pressure, the mixture is extracted with ethyl acetate (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was then purified liquid chromatography on 800 g of silica gel 60 (230 - 400 mesh.3.1 g (33) pure 1,2,3,4-tetrahydro-2-oxo-1-(2-propenyl)naphthalene in the form of a light yellow oil.

1H-NMR (CDCl3, MA): 7,27 7,16 (m, 4H), 5,81 of 4.95 (m, 3H), 3,54 of 2.45 (m, 7H).

IR (film):max(lambda max) 1717, 1640 and 1582 cm-1.

MS: M+186, other ions at m/z 168, 145, 128, 117.

TLC (silica gel GF): Rf0.51 in hexane-ethyl acetate (4 1).

From fractions 41 64 received 4,2 g (37) pure 1,2,3,4-tetrahydro-2-oxo-1,1-di(2-propenyl)naphthalene as a colourless oil.

Preparative example 14. 1,2,3,4-Tetrahydro-8-methoxy-2-oxo-1-(2-propenyl)naphthalene and 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-di(2-propenyl)naphthalene (E-2, scheme E).

To a solution of 8.8 g (50 mmol) of 8-methoxy-2-tetralone in 250 ml of THF in a three-neck flask equipped with gas inlet and a tube in a nitrogen atmosphere at -30oC add 40 ml of LDA (60 mmol, 1.5 M in cyclohexane). The solution is kept heated for 30 min to 0oC, then added to 6.5 ml (75 mmol) of allylbromide. The progress of the reaction is controlled by TLC. After stirring the mixture for 3 h at room temperature and 1 h at 40oC the mixture is neutralized by adding 10-aqueous sodium bisulfate to pH 2 to 3. After removal of THF under reduced pressure, the mixture is extracted with ethyl acetate (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and concentric further purification used in the next stage. For analytical purposes a small amount of crude product (<1 g) clear liquid chromatography 185 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (19 1). The pure title compound is isolated in the form of colourless oils.

Physical data for 1,2,3,4-tetrahydro-8-methoxy-2-oxo-2-(2-propenyl)naphthalene:

1H-NMR (CDCl3, TMS): 7,21 6,76 (m, 3H), 5,73 to 4.87 (m, 3H), 3,82 (s, 3H), 3,88 is 3.82 (m, 1H), 3,32 2,43 (m, 6H).

IR (film):max1712, 1640, 1586 cm-1.

MS: C14H16O2.

Calculated: 216, N 1150.

Found: 216, N 1151.

Analysis: C14H16O2.

Calculated: C 77,75, H 7,46.

Found: 77,56, H 7,68.

TLC (silica gel GF): Rf0.32 in hexane-acetone (4 1).

Physical data for 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-di(2-propenyl)naphthalene.

1H-NMR(CDCl3, TMS): 7,22 of 6.73 (m, 3H), 5,44 of 4.77 (m, 6H), 3,85 (s, 3H), 4 2,52 (m, 8H).

IR (film):max1712, 1639, 1582 cm-1< / BR>
MS: C17H20O2.

Calculated: 256, N 1463.

Found: 256, N 1470.

Analysis: C17H20O2.

Calculated: C Of 79.65, H 7,86.

Found: C 79,56, H 8,29.

TLC (silica gel CF): R is l)naphthalene (E-2, scheme E) and 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1,1-di(2-propenyl)naphthalene.

To a solution of 5.3 g (30 mmol) 5-methoxy-2-tetralone in 45 ml of THF in a three-neck round bottom flask equipped with a gas input tube, in a nitrogen atmosphere at -30oC add 22 ml of LDA (33 mmol, 1.5 M in cyclohexane). The solution is kept heated for 30 min to 0oC, and then added 3.4 ml (39 mmol) of allylbromide. The progress of the reaction is controlled by TLC. After a five-hour stirring, the reaction mixture is neutralized by adding 10-aqueous sodium bisulfate to pH 2 to 3. After removal of THF under reduced pressure, the mixture is extracted with ethyl acetate (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 800 g of silica gel 60 (230 to 400 mesh) by elution 1 l of hexane and 5 l of a mixture of hexane-ethyl acetate (19 1) and selected fractions of 40 ml Of fractions 45 87 obtained 2.5 g (32,5) pure 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1,1-di(2-propenyl)naphthalene in the form of almost colorless oil, and fractions 88 140 obtained 1.07 g (16,5) pure 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-(2-propenyl)naphthalene in the form of a light yellow oil.

1H-NMR (CDCl3FCM): 7.23 percent 6,77 (m, 3H)216, other species of m/z 175, 159, 147.

TLC (silica gel GF): Rf0,42 in hexane-ethyl acetate (4 1).

Preparative example 16. 1,2,3,4-Tetrahydro-8-methoxy-1-(cyclopropylmethyl)-2-oxonation (E-2, scheme E).

The solution to 3.52 g (20 mmol) of 8-methoxy-2-tetralone in 50 ml of THF in a three-neck round bottom flask equipped with a gas input tube, in a nitrogen atmosphere at -30oC add to 14.3 ml of LDA (22 mmol, 1.5 M in cyclohexane). The solution is kept heated for 30 min to 0oC, and then added 2.4 ml (24 mmol) of allylbromide. The progress of the reaction is controlled by TLC. After two hours stirring, the reaction according to TLC almost never starts. Therefore, the reaction mixture was treated with 1.1 ml (12 mmol) of Allbreed and the mixture is boiled for 72 hours, the Reaction mixture is neutralized by adding 10-aqueous sodium bisulfate to pH 2 to 3. After removal of THF under reduced pressure, the mixture is extracted with ethyl acetate (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (9 1) and selected fractions of 40 ml of the Homogeneous fractions (TLC) are combined and their concentration>NMR (CDCl3, TMS): 7,2 to 6.75 (m, 3H), 3,91 ( t, J 7 Hz, 1H), 3,81 (s, 3H), 3.33 and of 1.62 (m, 6H), 0,09 0,64 (m, 5H).

IR (film): max1711 cm-1.

MS: C15H18O2.

Calculated: 230, H 1307.

Found: 230, N 1290.

Analysis: C15H18O2.

Calculated: C 78,23, H 7,88.

Found: C 77,93, H 8,06.

TCX (silica gel GF): Rf0,46 in hexane-acetone (4 1).

Preparative example 17. Methyl ester of 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-naphthaleneboronic acid (F 2, diagram F).

To a solution of 17.6 g (0.1 mol) of 8-methoxy-2-tetralone in 200 ml of THF in a three-neck round bottom flask equipped with a gas input tube, in a nitrogen atmosphere at -30oC add to 86.7 ml of LDA (0.13 mol, 1.5 M in cyclohexane). The solution is kept heated for 30 min to 0oC, then add 84,3 ml (1 mol) of mimetikarea. After boiling for 24 hours (bath temperature 70oC) according to TLC original products are not available. The reaction mixture is neutralized by adding 1 N. HCl to pH 2 to 3. After removal of THF under reduced pressure, the mixture is extracted with methylene chloride (1 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and contentresult in vacuum. is on, 2 l of 10 and 8 l 20 ethyl acetate in hexane and selected fractions of 500 ml Of fractions 7 9 obtained 0.5 g (2) yellow oil, which according to the1H-NMR is 1,1-descarboethoxyloratadine. From fractions 11 22 received 21.1 g (90) of pure title compound as a yellow oil.

1H-NMR (CDCl3, TMS): 7,28 6,77 (m, 3H), 4.72 in (s, 1H), and 3.8 (s, 3H), 3.72 points 2,17 (m, 7H).

IR (film):max1750, 1718 and 1588 cm-1.

MS: M+234, other ions at m/z 202, 191, 174, 147, 131, 115, 103, 91.

Analysis: C13H14O4.

Calculated: C 66,65, H 602.

Found: C 63,49, H 5,93.

TLC (silica gel GF): Rf0.33 hexane-ethyl acetate (3 1).

Preparative example 18. Methyl ester of 1,2,3,4-tetrahydro-8-methoxy-2-oxo-3-(2-propenyl)-1-naphthaleneboronic acid (F-3, scheme F).

To a solution of 10.2 g (of 43.5 mmol) of the methyl ester of 1,2,3,4-tetrahydro-8-methoxy-1-naphthaleneboronic acid in 108 ml of THF in a three-neck round bottom flask equipped with addition funnel, under nitrogen atmosphere at a temperature of from -30oC -40oC added dropwise to 63.8 ml (or 95.7 mmol) of LDA (1.5 M in cyclohexane). The solution is allowed to warm to 0oC, then add 6 ml (69,6 mmol) allylbromide. After stirring 1 h at komnatnaya 3 N. hydrochloric acid to pH 2, 3, and extracted with ethyl acetate (2 x 1 l). The combined organic salts washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 800 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (3 1) and selected fractions of 40 ml Of fractions 36 63 obtained 10.3 g (87) of pure title compound as a yellow oil.

1H-NMR (CDCl3, TMS): 7,27 6,76 (m, 3H), of 5.89 5,02 (m, 3H), 4.75 in (two s, 1H), 33,8, 3,81 (two s, 6H), 3,3,2 of 1.64 (m, 5H).

IR (film): lambda max 1751, 1717 and 1589 cm-1.

MS: M+274, other ions at m/z 242, 233, 214, 201, 187, 173, 159, 145.

Analysis: C16H18O4.

Calculated: C 70,05, H 6,61.

Found: C 69,73, H Of 6.65.

TLC (silica gel GF): Rf0.34 in hexane-ethyl acetate (3 1).

Preparative example 19. 1,2,3,4-Tetrahydro-8-methoxy-3-(2-propenyl)-2-oxonation (F-4, scheme F).

To a solution of 10.3 g (of 37.6 mmol) of the methyl ester of 1,2,3,4-tetrahydro-8-methoxy-2-oxo-3-(2-propenyl)-1-naphthaleneboronic acid 26.3 ml DMSO and 1.1 ml of water is added to 1.9 g (45,1 mmol) of lithium chloride and the reaction mixture is heated 5 h at 125oC (bath temperature). By TLC analysis to determine the absence of the Isla washed with 10% aqueous solution of calcium sulfate effective way to remove DMSO from the organic layer), dried (MgSO4), filtered and concentrated in vacuo. The crude product was then purified liquid chromatography on 800 g of silica gel 60 (230 to 400 mesh) with elution by the mixture hexane-ethyl acetate (3 1) and selected fractions of 40 ml Of fractions 26 53 received of 7.65 g (94) of pure title compound as a yellow oil.

1H-NMR (CDCl3, SCI): 7,18 6,74 (m, 3H), 5,95 of 4.95 (m, 3H), 3,82 (s, 3H), 3,7 of 2.08 (m, 7H).

IR (film): lambda max 1756, 1710 and 1589 cm-1.

MS: M+216, other ions at m/z 185, 174, 159, 146, 134, 115, 104.

Analysis: C14H16O2.

Calculated: C 77,75, H 7,46.

Found: C 77,21, H 7,65.

TLC (silica gel GF): Rf0.53 in hexane-ethyl acetate (3 1).

Preparative example 20. Methyl ether ()-1,2,3,4 - Tetrahydro-8-methoxy-2-(2-propenyl)-N-[3-oxopropylidene)-1-natalymartynova acid (G-3, the diagram G).

A solution of CIS - and TRANS-isomers of methyl ester of 1,2,3,4-tetrahydro-8-methoxy-2-(2-propylamino)-1-naphthaleneboronic acid in the form of the free base in 5 ml of pyridine and 10 ml of methylene chloride is treated with 2.5 ml (20 mmol) of propionic anhydride. After stirring 3 h at room temperature TLC analysis shows the absence of the original products. For the destruction of excess re is up 10-s ' solution of sodium bisulfate, brine, 10-s ' solution of sodium hydroxide, brine, dried (MgSO4), filtered and after concentrating receive light yellow oil, which was purified LC with elution with a mixture of acetone-hexane (2 1) and selected fractions of 40 ml Of fractions 10 20 obtained 1.4 g (84) of the title compound.

1H-NMR(CDCl3, TMS): 7,2 6,6 (m, 3H), 5,9 5,1 (m, 3H), 4,85 4,3 (m, 1H), 4 to 3.6 (m, H in), 3.75 ( s, 3H), to 3.67 (s, 3H), 3,1 is 1.82 (m, 6H), of 1.17 (t, 3H).

Preparative example 21. 1,2,3,4-Tetrahydro-8-methoxy-T-hydroxymethyl-2-(2-propenyl-N-propylamino)naphthalene (C-4, scheme C).

In 40 ml of THF was dissolved 1,33 g (4 mmol) of the methyl ester of 1,2,3,4-tetrahydro-8-methoxy-2-[2-propenal-[2-oxopropyl] amino]naphthaleneboronic acid and the solution process of 0.91 g (24 mmol) of sociallyengaged. The mixture is boiled for 3 h, then neutralized with a saturated solution of sodium sulfate, diluted in 500 ml of THF, dried (MgSO4), filtered and concentrated receive oil. Oil cleanse LC with elution by the mixture hexane-acetone (2 1) and selected fractions of 40 ml Of fractions 24 28 obtained the title compound as a pale yellow oil, not crystallising after conversion into HCl-salt.

1H-NMR (CDCl3, TMS): 7,13 only 6.64 (m, 3H), 5,14 6 (m, 3H), 3,92 to 3.7 (m, 2H), 3,82 (m, 3H), 3,68 of 1.42 (m, 10H), and 0.9 (t, 3H).

Preparative example 23. 8-Bromo-2-(Spiro-1,2-dioxolane-2-yl)-tetralin (H-3, scheme H).

A mixture of 8-bromo-2-tetralone (29 g), ethylene glycol (24 g), p-toluenesulfonic acid (0.5 g) and benzene (50 ml) is boiled for 16 h with azeotropic removal of water. The solution is cooled and extracted with aqueous sodium carbonate solution, water and brine. The solution is dried over anhydrous sodium sulfate and the solvent is removed in vacuum.

Preparative example 24. 8-Trifluoromethyl-2-(Spiro-1,2-dioxolane-2-yl)-tetralin (H-4, scheme H).

A mixture of 8-bromo-2-(Spiro-1,3-dioxolane-2-yl)tetralin (12.4 g), triptoreline sodium (25 g), copper iodide (1) (17.5 g) and N-methylpyrrolidone (368 ml) is heated under nitrogen atmosphere for 4 h at 160oC. the Solution is cooled and added ether and hexane. The suspension is filtered through diatomaceous earth and the filtrate washed with water (3x) and brine. The solution is dried over anhydrous sodium sulfate and the solvent is removed in vacuum. Pressure chromatography with elution with a mixture of ether-hexane (1 9) gain of 9.9 g of pure liquid.

Preparative example 25. 8-Trifluoromethyl-2-tetralone (H-5, scheme H).

A mixture of 8-trifluoromethyl-2-(Spiro-1,3-dioxolane-2-l) tetralin (9,9 g), evgenichesky layer was washed with aqueous sodium bicarbonate solution and brine. Drying over anhydrous sodium sulfate and removal of solvent receive transparent liquid.

Preparative example 26. 8-Trifluoromethyl-2-amine derivatives in optically active form (H-6, scheme-N).

A mixture of 8-bromo-2-tetralone (15.2 g), (R)-(+)-alpha-methylbenzylamine (46 ml), acetic acid (added to pH 5), methanol (100 ml) and THF (100 ml) is stirred 30 min at 0oC. Then add cyanoborohydride sodium (9 g) and the reaction mixture was stirred 3 h at 0oC. the Solvent is removed in vacuum, the residue is transferred into a column for pressure chromatography with silica gel (5 cm wide) and outyouth a mixture of ethyl acetate-hexane (8 92 with the transition to 15 85). The diastereoisomer with a higher value of Rfsolidifies upon standing, and the diastereoisomer with a lower value of Rfremains in the form of butter.

Preparative example 27. Optically active 8-trifluoromethyl-2-N-[(R)-alpha-methylbenzyl]propionamide-2-elterlein (H-7, scheme H).

Note. Both diastereoisomer separately conducted through this stage. Product reductive amination (see above, 8,4 g) dissolved in methylene chloride (50 ml) and triethylamine (4 ml) and cooled to 0oC. Then add propionate (2.5 ml) and RAS is sodium and brine. Drying the organic layer over anhydrous sodium sulfate and removal of solvent in vacuo obtain 10.2 g of a transparent liquid.

Preparative example 28. Optically active 8-trifluoromethyl-2-N-[(R)--methylbenzyl]-2N-propylaminoethyl (H-8, scheme H).

Note. This operation is subjected to both diastereoisomer separately. In 60 ml of THF was dissolved 8-trifluoromethyl-2-N-[(R)-alpha-methylbenzyl]propionamide-2-yl-tetralin (10.2 g), add complex brandibelle (13,5 ml of 10 M solution) and the solution is boiled for 3 hours

The reaction mixture was cooled to 0oC and slowly added 2 n aq. HCl. Then add 3 N. aqueous solution of sodium hydroxide to pH 12 and the solution extracted with ether. The ether solution is washed with water and brine, the solvent is removed in vacuo, and the residue is transferred into the upper part of the column (1 cm) with silica gel for displacement chromatography and elute with ether. After distillation of the solvent to obtain 9 g of pure title compound.

Preparative example 29. 8-Aminosulfonyl-2-(Spiro-1,3-dioxolane-2-yl)tetralin (J-2, diagram J).

Covered in dry tetrahydrofuran (50 ml) to magnesium (3,83 g, 0,158 mol) added 8-bromo-2-(Spiro-1,3-dioxolane-2-yl)tetralin (28,29 g, 0,105 mol), EIT is the mixture is stirred at room temperature to terminate the reaction, then carefully heated to boiling on a water bath for 40 minutes a Solution of the Grignard reagent is separated from the excess of magnesium using a needle device and cooled to -15oC. Then through the solution for 30 min miss gaseous sulfur dioxide. The mixture is diluted with diethyl ether and washed with diluted hydrochloric acid and brine containing sodium bicarbonate. The solution is dried (MgSO4) and after removal of the solvent in vacuo get 27, 26 g sulfinol acid in the form of a snow-white solid.

(J 3, diagram J). To sodium hydride (5.3 g, 50 in oil, 0.11 mol), washed twice with hexane and covered with dry tetrahydrofuran (400 ml), using a needle fixture adds solution sulfinol acid (26,38 g, 0.104 g mol) in dry tetrahydrofuran (300 ml). The mixture is stirred for about a day at room temperature, then boiled for 15 minutes the Mixture is diluted with diethyl ether and the precipitate is filtered off with blowing of argon over the surface of the joint. The connection is washed several times with diethyl ether and after drying in a vacuum get 26,77 g sulfonate sodium in the form of a solid substance.

(J 4, diagram J). Suspension of sulfonate sodium (26,77 g, 0,0969 mol) in chloride metanol temperature, then add diethyl ether and the mixture is washed with water and brine. The solution is dried (MgSO4) and after removal of the solvent in vacuo obtain 23.3 g of sulphonylchloride in the form of a solid amber color.

(J 5, diagram J). It chilled with ice to a solution of ammonium hydroxide (100 ml) in acetone (500 ml) add a solution of sulphonylchloride (23.3 g), bath with ice is removed and the mixture is stirred for 2 hours the Solution is evaporated and the residue is partitioned between a mixture of diethyl ether-tetrahydrofuran (4 1) and brine. The solution is twice washed with 2-Noah hydrochloric acid, saturated sodium bicarbonate solution and brine, dried (MgSO4) and after removal of the solvent in vacuo get 19,8 g sulfonamida in the form of a brown solid. A sample of the product (0.75 g) is crystallized from a mixture of ethyl acetate-hexane and get the snow-white crystals sulfonamida (0.68 g) so pl. 127 128oC.

Preparative example 30. 8-Aminosulfonyl-2-tetralone (J-6, scheme J).

In 400 ml of acetone was dissolved 8-aminosulfonyl-2-(Spiro-1,3-dioxolane-2-yl)-tetralin (18,36 g, 0,0682 mol), to the solution was added p-toluensulfonate (1.85 g, 9.7 mmol, 14 mol.) and the mixture is stirred for 21 h at room temperature. Then add a saturated solution bicarbonate, washed with water and dried in vacuum. The connection is boiled in ethyl acetate (350 400 ml) until dissolution of the greater part of the solids and then filtered. The addition of hexane to cause crystallization of the ketone in the form of an orange substance (10,34 g) so pl. 173 175oC.

Example 1. 1,2,3,4-Tetrahydro-2-N-propylaminoethyl-8-yl-carboxamide (9, scheme a).

A mixture of 1,2,3,4-tetrahydro-2-oxonation-8-ylcarboxamine (1.8 g, 9.5 mmol), acetic acid (2,27 ml, 4 equiv.) N-Propylamine (3.12 ml, 4 equiv.) laborgerate sodium (900 mg) and methanol (15 ml) is stirred for 2 h at 25oC. Then add ether (100 ml) and the solution washed with saturated aqueous sodium bicarbonate (30 ml), water (50 ml) and brine (30 ml) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo get white foam. Crystallization of the hydrochloride from methanol-ether to obtain the title compound as white needles (so pl. 225oC).

According to the method of example 1, but using the corresponding amine instead of N-Propylamine obtained the following compounds: 1,2,3,4-tetrahydro-2-N-(2-propenyl)aminonaphthalene-8-ylcarbonyl, recrystallized in the form of a salt with maleic acid from acetonitrile (so pl. 136oC); 1,2,3,4-tetrahydro is from methanol-diethyl ether (so pl. 112oC).

Example 2. 1,2,3,4-Tetrahydro-2-N - cyclopropylmethanol-8-ylcarbonyl, oxalate.

Use a technique similar to the technique of example 1, but instead carboxamide using a corresponding N-methylcarbamic and receive the title compound, recrystallized in the form of oxalate from methanol-diethyl ether (so pl. 225oC, decomp.).

Example 3. 1,2,3,4-tetrahydro-2-N,N-dipropylamino-8-ylcarbonyl (A-10, scheme A) (compound 3A).

A mixture of 1,2,3,4-tetrahydro-2-N-propylaminoethyl-8-ylcarboxamine (1.3 g, 5.6 mmol), sodium carbonate (712 mg), n-bromopropane (0,66 ml) and acetonitrile (15 ml) was boiled for 30 hours and Then the reaction mixture is cooled and transferred into a mixture of methylene chloride (50 ml) and ether (50 ml). The resulting mixture was extracted with water (2 x 50 ml) and brine (50 ml) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo get to 1.38 g (yield 90) product. The title compound crystallized as the hydrochloride from methanol-ether (so pl. 142oC).

According to the method similar to example 2, the obtained 1,2,3,4-tetrahydro-2-N-n-propyl-N-cyclopropylmethanol-8 - ylcarbonyl, recrystallized in the form of fumarata from methanol-ether (so methylcarbamate (compound 4A).

According to the method of example 3, but using 1,2,3,4-tetrahydro-2-N-cyclopropylmethanol-8-hilderbrand and bromelicola obtained the title compound I. pl. 120oC from a mixture of ethyl acetate-hexane.

In addition, using the method of example 3, but replacing them with the appropriate carboxamide and golozhabernyi derivatives, the following compounds: 1,2,3,4-tetrahydro-2-N, N-di-n-propylaminoethyl-8-yl-N-benzyloxycarbonylglycine, salt with maleic acid (so pl. 147oC) (compound 4B); 1,2,3,4-tetrahydro-2-N, N - dicyclopentadienyl-8-yl-N-methylcarbamate (so pl. 120oC) (compound 4C), salt with maleic acid (compound 4d).

Example 5. By the method similar to the method of example 2, but replacing n-bromopropane appropriate haloalkane, and where necessary N-propylaminoethyl corresponding N-alkylaminocarbonyl obtained the following compounds: 1,2,3,4-tetrahydro-2-N-n-propyl-2-N-[4-(2,3-dihydro-1,1-dioxo-3-benzisothiazolin)butyl] naphthalene-8-ylcarbonyl, recrystallized in the form of a white foam (so pl. 80oC) (compound 5A); 1,2,3,4-tetrahydro-2-N-cyclopropylmethyl-2-N-propylaminoethyl-8-ylcarbonyl, recrystallized from a mixture of metasome (so pl. 229oC) (compound 5B).

Example 6. (1,2,3,4-Tetrahydro-2-N - propylaminoethyl-8-yl)-(2-pyrrolyl)ketone (B-3, scheme B) (compound 6).

In the apparatus Parra mix (1,2,3,4 - tetrahydro-2-oxonation-8-yl)(pyrrol-2-yl)ketone (2,27 g, 9.5 mmol, obtaining see preparative example 8), N-Propylamine (3.12 ml, 4 equiv.) acetic acid (2,17 ml, 4 equiv.) the platinum oxide (200 mg) and absolute methanol (30 ml) and stirred for 3 hours Create a hydrogen pressure of 50 psi (3.5 kg/cm2) and the mixture shaken for 3 h, then filtered and the solvent is removed in vacuum. The residue is extracted with ether (150 ml) and saturated aqueous sodium carbonate (25 ml). The organic layer was washed with water (50 ml) and brine (50 ml) and dried over anhydrous solution of sodium.

Removal of solvent in vacuo get the foam, the crystallization of which is in the form of the hydrochloride from methanol-ether to obtain the title compound in the form of needles (so pl. 256oC).

Example 7. (1,2,3,4-Tetrahydro-2-N,N - dipropylamino-8-yl)(2-pyrrolyl)ketone (B-4, scheme B) (compound 7).

A mixture of 1,2,3,4-tetrahydro-2-N-propylaminoethyl-8-yl)(2-pyrrolyl)ketone (1,58 g, 5.6 mmol), sodium carbonate (712 mg), n-bromopropane (0,66 ml) and acetonitrile (10 ml) is boiled for 24 hours and Then the reaction mixtures which provide water (2 x 50 ml), brine (50 ml), dried over anhydrous sodium sulfate and the solvent is removed in vacuum. The residue is transferred to the column for pressure chromatography with silica gel (2 cm x 40 cm) and elute with a mixture of ethyl acetate-hexane (serial transition from 15 to 85 20 80 and 40 60). Removal of solvent in vacuo get a dark oil, which upon standing cures in the title compound (so pl. 75oC).

Example 8. 8-Methoxy-N-propyl-N-[3-(2,3-dihydro-1,1-dioxo-3-oxo-1,2-benzisothiazolin)propyl]-2-aminotetralin (U-81349).

A mixture of 8-methoxy-N-propyl-2-aminotetraline (see Arvidsson L. E., and others J. Med. Chem. 27, 45, 1984) (2 g, 10 mmol), N-(3-improper)-2,3-dihydro-1,1-dioxo-3-benzisothiazolin (7.5 g), sodium carbonate (2.5 g) and acetonitrile is boiled for 24 hours After cooling, the solvent is removed in vacuo, and the residue is transferred to the column for pressure chromatography with silica gel (2 cm x 35 cm) and elute with a mixture of ethyl acetate-hexane (consistently 5 95, 10 90, 15 85, 20 80). After removal of solvent in vacuo receive the title compound as a white powder (so pl. 131oC).

Example 9. 8-Methoxy-N-propyl-N-[4-(2,3 - dihydro-1,1-dioxo-3-oxo-1,2-benzisothiazolin)butyl]-2-aminotetralin.

By the method similar to the method of example 8, tx2">

Example 10. 8-Methoxy-N-propyl-N-[5-(2,3-dihydro-1,1-dioxo-3-oxo-1,2-benzisothiazolin)pentyl]-2-aminotetralin.

By the method similar to example 8 are in the form of butter 8-methoxy-N-propyl-N-[5-(2,3-dihydro-1,1-dioxo-3 - oxo-1,2-benzisothiazolin)pentyl]-2-aminotetralin.

Example 11. 8-Hydroxy-N-propyl-N-[3-(2,3-dihydro-1,1-dioxo-3-oxo-1,2-benzisothiazol]propyl]-2-aminotetralin.

8-methoxy-N-propyl-N-[3-(2,3-dihydro-1,1-dioxo-3-oxo-1,2-benzisothiazol)propyl] -2-aminotetraline (2,12 g and 4.65 mmol) and 48-Noah Hydrobromic acid (20 ml) is heated for 20 minutes at 135oC. Then the solvent is removed in vacuo and the residue partitioned between ether (100 ml) and ammonium hydroxide (100 ml). The organic layer was washed with water (2 x 100 ml) and brine (50 ml) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo get the oil that is transferred into a column for pressure chromatography with silica gel (3 cm x 35 cm) and elute with a mixture of ethyl acetate-hexane (25 75). Removal of solvent in vacuo followed by crystallization of the hydrochloride from methanol-ether to obtain the title compound in the form of fine white powder so pl. 191oC.

Example 12. 8-Hydroxy-N-propyl-N-[4-(2,3-dihydro-1,1-dioxo-3-oxo-1,2 relevant aminotetraline, get 8-hydroxy-N-propyl-N-[4-(2,3-dihydro-1,1-dioxo-3-oxo-1,2-benzisothiazolin)butyl]-2-aminotetralin, recrystallized in the form of hydrochloride (so pl. 262oC) and 8-hydroxy-N-propyl-N-[5-(2,3-dihydro-1,1-dioxo-3-oxo-1,2-benzisothiazolin)pentyl-2-aminotetralin, recrystallized in the form of hydrochloride (so pl. 169oC) (12a).

Example 13. 8-Cyano-N,N-dipropyl-2-aminotetralin.

In 15 ml of methylene chloride was dissolved 8-carboxamide, N,N-dipropyl-2-aminotetralin (1 g, 3.6 mmol) and the resulting solution portions over 20 min add salt Burgess (internal salt of methyl(carboxylphenyl)-triethylaminooxide, see "Organic Synthesis", 56, 40 C.) (2.4 g). The reaction mixture is stirred for 3 h, and then transferred directly into a column for pressure chromatography with silica gel (2 cm x 35 cm) and elute with a mixture of ethyl acetate-hexane (30 70). Removal of solvent in vacuo obtain 0.87 g of oil which crystallized from methanol-ether (so pl. 158oC).

Example 14. 8-Cyano-N-cyclopropyl-N-2-aminotetralin synthesized by the above method (so pl. 158oC).

Example 15. ()-Octahydro-1-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalene)Asotin, hydrochloride (compound 15a).

To a solution of 1,7 - . The reaction mixture was stirred for 15 min in an atmosphere of N2, then added 1.26 g (20 mmol) NaCNBH3. At the end according to the TLC of the reaction (24 h) to neutralize the reaction mixture was added 1 N. NaOH (25 ml) and H2O (200 ml). The solution is extracted with CH2Cl2(2 x 500 ml), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (5 1). Fractions homogeneous according to TLC, are combined and after concentration in vacuum to get pure compound in the form of oil. Salt with HCl is obtained using HCl solution in MeOH. The title compound is isolated in the form of a white substance by recrystallization from E10Ac-MeOH (2.65 g, 86), so pl. 211 213oC.

1H-NMR (CDCl3, TMS): 7,13 (t, 1H), 6,69 (t, 2H), 3,81 (s, 3H), of 3.54 (m, 3H), 3,31 3,18 (m, 3H), 2,94 to 2.67 (m, 4H), 2,17 (m, 2H), 2,1 of 1.46 (m, 8H).

IR (paste): lmax2529, 2503, 1585, 1470, 1463, 1453, 1251 cm-1.

Analysis: C18H27NO HCl.

Calculated: C 9,769, H 9,108, N 4,521.

Found: C 69,6, H 9,24, N 4,65.

By the method similar to the method of example 15, but replacing heptamethylnonane the corresponding amine is obtained in the form of a white substance so pl. 184 184,5oC (compound 15b).

1H-NMR(CDCl3, TMS): to 7.15 (t, 1H), 6,7 (K, 2H), from 5.29 (s, 2H), 3,83 (s, 3H), of 3.65 (m, 2H), 3,4 3,2 (m, 3H), of 2.97 (m, 2H), 2,8 2,77 (m, 3H), of 2.16 (t, 2H), and 1.9 (m, 1H), and 1.6 (s, 3H).

IR (paste):max2867, 2855, 2556, 2541, 1648, 1589, 1443 cm-1.

Analysis: C16H23NO HCl.

Calculated: C 68,435, H 8,256, N 4,988.

Found: C 68,23, H 8,46, N To 5.21.

()-N-(1,2,3,4-Tetrahydro-8-methoxy-2-naphthalene)glycine, ethyl ester, hydrochloride as a white solid (compound 15c).

()-5-Methoxy-N-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)-1H-indol-3-alamid, monohydrochloride, white substance, so pl. 203 204oC (compound 15g).

1H-NMR (CDCl3, TMS): 7,28 of 6.7 (m, 7H), of 3.84 (s, 3H), 3,81 (s, 3H), 3,62 1,72 (m, 11H).

IR (paste):max3260, 1608, 1590 cm-1.

Analysis: C22H26O2HCl.

Calculated: C 68,29, H 7.03 Is, N 7,24.

Found: C 68,31, H 7,09, N 7,24.

()-TRANS-3,5-dimethyl-1-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)piperidine, hydrochloride, white matter, 1.78 g (33), so pl. 230 232oC.

1H-NMR (CDCl3, TMS): 7,09? 7.04 baby mortality (t, 1H), of 6.71 6,6 (K, 2H), 3,82 (s, 3H), 2,87 of 2.27 (m, 9H), 1.91 a (m, 2H), 1,6 (m, 2H), 1,32 1,28 (m, 2H), and 0.98 (s, 3H), of 0.87 (s, 3H).

IR (paste):max3005, 3035, 2200, 1590 and 1460 cm-1.

/P>CIS-3,5-dimethyl-1-(1,2,3,4-tetrahydro-8-methoxy-2-naftalin)piperidine, hydrochloride, white substance of 2.36 g (43), so pl. 231 233oC.

1H-NMR (CDCl3, TMS): 7,14 (t, 1H), 6,77 6,67 (K, 2H), 3,82 (s, 3H), 3,6 to 3.36 (m, 4H), 2,96 (m, 2H), 2,75 (m, 4H), 2,45 (K, 1H), 2,3 (K, 1H), and 1.9 (m, 2H), by 1.68 (m, 1H), 0,99 (s, 3H), of 0.97 (s, 3H).

IR (paste):max3005, 3035, 2200, 1590 and 1460 cm-1.

Analysis: C18H27NO HCl.

Calculated: C 69,77, H Remaining 9.08, N 4,77.

Found: C 69,71, H Remaining 9.08, N 4,77.

3,5-Dimethyl-1-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)piperidine, hydrochloride, white matter, so pl. 200oC (connection 15h).

1H-NMR (CDCl3, TMS): to 7.15 (t, 1H), 6,69 (t, 2H), 3,83 (s, 3H), 3,71 (m, 1H), 3,5 2,3 (m, 9H), and 1.6 (s, 6H), of 1.53 (m, 2H), and 0.98 (m, 3H).

IR (paste):max3000, 2450 cm-1.

Analysis: C18H27NO HCl.

Calculated: C 68,77, H 9,11, N To 4.52.

Found: C 68,99, H 9,07, N 4,67.

()-N-Ethyl-1,2,3,4-tetrahydro-8 - methoxy-N-2-propenyl-2-naphtylamine, hydrochloride, white solid.

1H-NMR (CDCl3, TMS): 7,14 (t, 1H), 6,7 (K, 2H), 6.35mm (m, 1H), 5,54 5,416 (m, 2H), 3,82 (s, 3H), 3.75 to to 3.49 (m, 2H), 3,19 (m, 2H), 2,96 (m, 2H), 1,99 (m, 1H), of 1.66 (m, 2H), 1,57 1,49 (m, 3H), 2,75 2,7 (m, 2H).

IR (paste):max2474, 1647, 1603, 1584, 1473, 1466, 1400 and 1257 cm-1.

Analysis: C16H23NO H/SUB> 0.59 in hexane-acetone (3 1).

1,2,3,4-Tetrahydro-8-methoxy-N-methyl-N-2-propenyl-2-naphtylamine, hydrochloride, white solid, so pl. 191 192oC (compound 15i).

1H-NMR (CDCl3, TMS): 7,16 (m, 1H), 6.75 in 6,69 (m, 2H), 6,45 (m, 1H), 5,55 (m, 2H), 3,83 (s, 3H), 3,81 of 3.5 (m, 2H), 3,1 3,5 (m, 6H), and 1.9 (m, 1H), 1,61 (s, 3H).

IR (paste):max2469, 1644, 1604, 1586, 1472, 1434 and 1251 cm-1.

Analysis: C15H21NO HCl.

Calculated: C 67,277, H 8,281, N 5,231.

Found: C 67,33, H 8,25, N 5,58.

TLC (silica gel GF): Rf0.5 V hexane-acetone (3 1).

()-1,2,3,4-tetrahydro-8-methoxy-N-(phenylmethyl)-2-naphtylamine, hydrochloride, white matter, so pl. 219,8oC (compound 15j).

1H-NMR (CDCl3, TMS): 7,37 of 7.24 (m, 5H), was 7.08 (t, 1H), 6,68 (K, 2H), of 3.97 (s, 2H), 3,81 (s, 3H), 3,1 (LW. d, 1H), 2,99 of 2.7 (m, 3H), 2,38 (K, 1H), 1,66 1,55 (m, 3H).

IR (paste):max2440, 1604, 1590, 1500, 1469, 1313, 1300 and 1264 cm-1.

Analysis: C18H21NO HCl.

Calculated: C 71,57, H 7,29, N 4,611.

Found: C 70,68, H 7,47, N 4,76.

TLC (silica gel GF): Rf0,38 in a mixture of hexane-acetone (4 1).

()-N-Cyclohexyl-1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine, hydrochloride, white matter, so pl. 247 248oC (connection 15k).

1H-NMR (CDCl3, TMS): 7,13 (t,K (paste):max2645, 2582, 2487, 2390, 1931, 1604, 1589 1472, 1437 and 1253 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,067, H 8,859, N 4,735.

Found: C 68,46, H 8,99, N 4,82.

TLC (silica gel GF): Rf0,39 in a mixture of hexane-acetone (4 1).

N-Cycloheptyl-1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine, hydrochloride, white matter, so pl. 234 236oC (connection 15l).

1H-NMR (CDCl3, TMS): 7,12 7,07 (t, 1H), 6,69 6,63 (K, 2H), of 3.78 (s, 3H), 3,41 3,3 (m, 3H), 2,96 2,87 (m, 3H), and 2.6 (m, 1H), 2,45 (m, 1H), 2,1 2,25 (m, 2H), 2,1 to 1.87 (m, 4H), 1,65 of 1.4 (m, 8H).

IR (paste:max2490, 1602, 1586, 1529, 1470, 1455, 1436, 1257 cm-1.

Analysis: C18H27NO HCl.

Calculated: C 69,77, N. 9,10, N To 4.52.

Found: C 69,76, H 9,17, N 4,76.

N-(1,1-Dimethyl-2-PROPYNYL)-1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine, hydrochloride, white matter, so pl. 225 227oC (connection 15m).

1H-NMR (CDCl3, TMS): 7,17 for 7.12 (t, 1H), 6,7 6,6 (t, 2H), a 3.87 (s, 3H), to 3.67 (m, 1H), 3,37 (m, 1H), 2,97 of 2.8 (m, 3H), of 2.56 (m, 1H), 2.05 is (m, 1H) and 1.83 (s, 3H), equal to 1.82 (s, 3H).

Analysis: C16H21NO HCl.

Calculated: C 68,681, H 7,926, N 5,006.

Found: C 68,46, H Compared To 8.26, N 5,15.

()-1,2,3,4-Tetrahydro-8-methoxy-N-(2-methyl-2-propenyl)-2-naphtylamine, hydrochloride, white matter, so pl. 175 177oC (connection 15n).

IR (paste): max2950, 2655, 2409, 1610, 1600, and 1440 cm-1.

Analysis: C15H21NO HCl.

Calculated: C 67,277, H 8,281, N 5,23.

Found: C 67,37, H 8,46, N To 5.21.

()-N-(1-Ethylpropyl)-1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine, hydrochloride, white matter, so pl. 174 175oC (connection 15o).

1H-NMR (CDCl3, TMS): 7,1 (t, 1H), 6,7 6,63 (K, 2H), of 3.77 (s, 3H), 3.49 points to 3.3 (m, 2H), 3,25 (m, 1H), 3,05 2,89 (m, 3H), 2,27 2,1 (m, 1H).

IR (paste):max2900, 2850, 2519, 2467, 1600, 1475 and 1460 cm-1.

Analysis: C16H25NO HCl.

Calculated: 67,706, H 9,234, N 4,935.

Found: C 67,79, H 9,46, N Is 5.06.

N-Cyclobutyl-1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine, hydrochloride, white matter, so pl. 198 202oC (connection 15p).

1H-NMR (CDCl3, TMS): 7,12 7,06 (t, 1H), 6,7 6,66 (K, 2H), 3,81 (s, 3H), 3,57 (d, 2H), 3,2 3,03 (m, 2H), 2,86 (m, 2H), 2,21 (t, 1H), 2 (m, 1H), 1,61 (m, 1H).

IR (paste):max2950, 2910, 2860, 2400, 1600, 1460 cm-1.

Analysis: C15H21NO HCl.

Calculated: C 67,277, H 8,281, N 5,231.

Found: C 67,18, H 8,39, N 5,16.

N-(1,2,3,4-Tetrahydro-8-methoxy-2-naphthalenyl)bicyclo [2,2,1]-heptane-2-amine, hydrochloride, white matter, so pl. 254 256oC (connection 15q).

1H-NMR (CDCl3,):max2945, 2600, 2455, 2420, 1602, 1587, 1460 cm-1.

Analysis: C18H25NO HCl.

Calculated: C 70,226, H 8,513, N 4,55.

Found: C 69,92, H 8,73, N 4,59.

()-Hexahydro-1-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)-1H-azepine, hydrochloride, white matter, so pl. 236 237oC (connection 15r).

1H-NMR (CDCl3, TMS): 7,12? 7.04 baby mortality (t, 1H), of 6.71 6,64 (K, 2H), 3,81 (s, 3H), 3,03 was 2.76 (m, 7H), 2,45 (K, 1H), 2 (m, 1H), 1,62 (m, 10H).

IR (paste):max3000, 2600, 2550, 1590, 1480 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,017, H 8,859, N 4,735.

Found: C 68,91, H 9,04, N 4,57.

TCX (silicagel GF): Rf0.3 hexane-acetone (4 1).

()-N-Ethyl-1,2,3,4-tetrahydro-8-methoxy-N-(2-methyl-2-propenyl)-2-naphtylamine, hydrochloride, white matter, so pl. 155 156oC (connection 15s).

1H-NMR (CDCl3, TMS): 7,1 7,4 (t, 1H), of 6.71 6,64 (K, 2H), is 4.93 (s, 1H), 4,79 (s, 1H), 3,82 (s, 3H), 3,06 (s, 2H), 2,93-of 2.86 (m, 4H), 2,59 2,53 (m, 4H), 2 (m, 1H), 1,74 (s, 3H), and 1.56 (s, 3H), 1,06 1,01 (t, 3H).

IR (paste):max3078, 2950, 2420, 1648, 1591 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,017, H 8,859, N 4,735.

Found: C 67,67, H 8,77, N 4,73.

()-1,2,3,4-Tetrahydro-8-methoxy-N-[[3-(trifluoromethyl)-phenyl]methyl]-2-naphtylamine, hydrochloride, white wishesto">

Analysis: C19H20NOF3HCl.

Calculated: C 67,844, H 6,293, N 4,164.

Found: C 58,50, H Of 5.29, N 4,01.

3,3-Dimethyl-1-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)piperidine, hydrochloride, white matter, so pl. 223 229oC (connection 15u).

1H-NMR (CDCl3, TMS): 7,09? 7.04 baby mortality (t, 1H), of 6.71 6,63 (K, 1H), 3,81 (s, 3H), 2,8 (m, 4H), of 2.56 (m, 3H), of 2.23 (s, 2H), 2 (m, 1H), 1,6 (m, 4H), 1,25 (m, 2H), 0,95 (s, 3H), were 0.94 (s, 3H).

IR (paste): max2500 and 1590 cm-1.

Analysis: C18H28NO HCl.

Calculated: C 69,543, H 9,403, N 4,506.

Found: C 67,53, H 9,18, N 4,88.

4-(1,2,3,4-Tetrahydro-8-methoxy-2-naphthalenyl)thiomorpholine, hydrochloride, white matter, so pl. 259 260oC (connection 15v).

1H-NMR (CDCl3, TMS): 7,1 7,05 (t, 1H), of 6.71 6,64 (K, 2H), 3,81 (s, 3H), 2,97 of 2.7 (m, 12H), 2,53 2,44 (K, 3H), of 1.98 (m, 1H), 1,7 for 1.49 (m, 2H).

IR (paste):max2609, 2474, 1602, 1590, 1473, 1417 and 1257 cm-1.

Analysis: C15H21NOS HCl.

Calculated: C 60,084, H 7,386, N 4,672.

Found: C 59,15, H 7,50, N 4,70.

1,2,3,4-Tetrahydro-8-methoxy-N, N-di-2-propenyl-2-naphthalamine, hydrochloride (2.1 g, 83), hygroscopic foam (connection 15w).

1H-NMR (CDCl3, TMC): 7,1 7,05 (t, 1H), of 6.71 6,60 (K, 2H), 5,96 of 5.81 (m, 2H), 5,24 of 2.09 (m, 4H), 3,91 (s, 3H), 3.27 to 3,24 (m, 4H), 3.04 from a 2.9 (m, 2H), /P> Analysis: C17H25NO Hcl.

Calculated: C 69,40, H 8,23, N 4,76.

Found: C 67,65, H Of 7.48, N 5,86.

1,2,3,4-Tetrahydro-8-methoxy-N-2-propenyl-2-naphtylamine, hydrochloride, white matter, so pl. 179 181oC (connection C).

1H-NMR (CDCl3, TMC): 7,11 7,06 (t, 1H), 6.73 x 6,64 (K, 2H), 6,02 of 5.89 (m, 1H), 5,24 5,08 (K, 2H), 3,81 (s, 3H), 3,4 to 3.38 (d, 2H), 3,12 3,05 (LW. d, 1H), 2,95 of 2.83 (m, 3H), 2,28 2,36 (K, 1H) 2,01 (m, 1H), 1,63 1,54 (m, 1H).

IR (paste):max1610, 1590, 1460 cm-1.

Analysis: C14H19NO HCl.

Calculated: C 66,26, H 7,94, N 5,52.

Found: C 65,80, H 8,10, N 5,63.

1,2,3,4-Tetrahydro-8-methoxy-N-2-PROPYNYL-2-naphtylamine, white matter, so pl. 84 85oC (connection 15y).

1H-NMR (CDCl3, TMC): 7,13 7,07 (t, 1H), 6,69 6,63 (K, 2H), 3,9 (m, 1H, in), 3.75 (s, 3H), 2,89 2,3 (m, 10H), 2 (m, 2H), 1,7 (m, 1H).

IR (paste): max3250, 3190, 1475, 1425, 1370 cm-1.

Analysis: C14H17NO.

Calculated: C 77,60, H A 7.92, N 7,25.

Found: C 77,88, H 8,73, N 6,89.

1,2,3,4-Tetrahydro-8-methoxy-N, N-di-2-PROPYNYL-2-naphtylamine, hydrochloride, white matter, so pl. 182 183oC (connection 15z).

1H-NMR (CDCl3, TMC): 7,11 7,06 (t, 1H), 6,72 6,64 (K, 2H), 3,83 (s, 3H), 3,68 (s, 4H), 3,1 3 (m, 1H), 2,9 2,8 (m, 3H), 2,53 - 2,44 (4m, 1H), 2,24 2,17 (m, 3H), 1,67 1,57 (m, 1H).

IR 70,46, H OF 6.96, N OF 4.83.

Found: C 70,33, H 7,32, N 5,13.

()-CIS - and TRANS-2,6-dimethyl-4-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)morpholine.

Selected pure CIS-isomer (compound 15aa) of the title compound in the form of oil and the TRANS-isomer (compound 15 bb) of the title compound as a white substance, so pl. 72 74oC.

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMC): 7,17 (t, 1H), 6,7 6,6 (K, 2H), 3,82 (s, 3H), 3,7 3,5 (m, 2H), 3-2,4 (m, 8H), 2 (K, 1H), and 1.9 (m, 2H), 1,5 (m, 1H), 1,2 (s, 3H), 1,19 (s, 3H).

IR (paste): max1590, 1480 cm-1.

Analysis: C17H25NO.

Calculated: C 74,145, H 9,15, N 5,087.

Found: C 7317, H 9,17, N 5,1.

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMC): 7,14 (t, 1H), 6,66 6,64 (K, 2H), 3,82 (s, 3H), 3,76 3,68 (m, 2H), 3,06 3,01 (K, 1H), 2,93 2,78 (m, 4H), 2,66 2,61 (m, 1H), 2,5 2,44 (K, 1H), 2,18 of 2.09 (m, 1H), 2,08 2,03 (m, 2H), 1,58 of 1.45 (m, 1H), 1,22 (s, 3H), to 1.21 (s, 3H).

IR (paste):max1603, 1590 and 1480 cm-1.

Analysis: C17H25NO2.

Calculated: C 74,145, H 9,15, N 5,087.

Found: C 7394, H Of 9.30, N 5,04.

8-Chloro-6-phenyl-N-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)-4H-[1,2,4] triazolo[4,3-a] [1,4] benzodiazepine-1 - methylamine, snow-white substance, so pl. 138 150oC (compound 15 cc3,1 to 3.7 (m, 5H), 2,4 (m, 1H), 2 (m, 4H), 1,7 (m, 1H).

IR (paste): max2900, 2640, 1600, 1590, 1490, 1460 cm-1.

Analysis: C28H26N5OCl.

Calculated: C 69,49, H 5,41, N 14,47.

Found: C 68,71, H Of 5.82, N 13,92.

Example 16. ()-7-(1-Ethylpropylamine)-5,6,7,8-tetrahydro-1-naphthalenol, hydrochloride (C-3, scheme C) (compound 16a).

A solution of 1 g (3.5 mmol) of the hydrochloride of N-(1-ethylpropyl)-1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine and 20 ml of 48-Noah HBr heated at 110oC and then boiled for 24 hours Upon completion of the reaction (TCX) add 20 NaOH and H2O to pH 13. The mixture is extracted with EtOAc (3 x 400 ml) and the combined organic salts washed with brine, dried (MgCO4), filtered and after concentrating receive the product. By recrystallization from EtOAc-MeOH receive 0.85 grams (91) of the title compound as a white substance so pl. 268oC.

1H-NMR (CDCl3, TMC): 7,1 (t, 1H), 6,65 (t, 1H), 3,5 3,37 (m, 3H), 3,36 3,2 (m, 2H), 3,1 2,9 (m, 2H), 2,7 (K, 1H), 2,35 (m, 1H) and 1.83 (m, 4H), 1,08 1,03 (m, 6H).

IR (paste):max3206, 1584, 1466 cm-1.

Analysis: C15H23NO HCl.

Calculated: C 66,77, H 8,966, N 5,19.

Found: C 66,32, H 8,72, N Lower Than The 5.37.

()-TRANS-7-(3,5-dimethyl-1-piperidinyl)-5,6,7,8-tetrahydro-1-naphthalenol, hydrochloride (0,62 g, 65) so pl. 273 276oC (connect the ptx2">

IR (paste):max3328, 3047, 2816, 1629, 1488, 1460, 1440 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,02, H 8,859, N 4,735.

Found: C 66,15, H 8,43, N 4,82.

()-CIS-7-(3,5-Dimethyl-1-piperidinyl)-5,3,7,8-tetrahydro-1-naphthalenol, hydrochloride (0,63 g, 67) so pl. 292 295oC (compound 16c).

1H-NMR (CDCl3, TMC): of 6.96 (t, 1H), 6,67 to 6.57 (d, 2H), 3,6 2,7 (t, m, 8H), 2,2 1,7 (m, 6H), 1,22 (s, 3H), 1,1 (s, 3H).

IR (paste)max3093, 3014, 2551, 1590, 1433 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,02, H 8,859, N 4,735.

Found: C 68,58, H 8,97, N 4,69.

Example 17. ()-7-(Hexahydro-1(2H)-azocine)-5,6,7,8-tetrahydro-1-naphthalenol, hydrochloride (C-3, scheme C) (compound 17).

A solution of 1 g of hydrochloride ()-hexahydro-1-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalene)-1H-azepine and 20 ml of HBr 48 is heated to 110oC and boiled for 24 hours Upon completion of the reaction (TCX) add 20 NaOH and H2O to pH 13. The mixture is extracted with EtOAc (3 x 400 ml) and the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated to obtain the product. Using HCl solution in MeOH receive HCl-salt. By recrystallization from EtOAc-meOH get 0,73 (77) of the title compound as a white substance so pl. 211 213oC.

ptx2">

IR (paste):max3127, 2953, 2855, 2615, 2563, 1594, 1467 cm-1.

Analysis: C16H23NO HCl.

Calculated: C 68,19, H 8,58, N Equal To 4.97.

Found: C 67,98, H 8,80, N Equal To 4.97.

Example 18. ()--Methyl-N-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)-1,3-benzodioxol-5-ethylamine hydrochloride (compound 18).

To a solution of 1 g (5.6 mmol) of 8-methoxyaminomethyl and 4.2 ml (28 mmol) of [3,4-methylenedioxy)phenyl] -2-propanone in 30 ml of MeOH-THF (1 1) to establish a pH of 4 to 5 added dropwise HOAc. The reaction mixture was stirred for 15 min in an atmosphere of N2, then add 0.7 g in (11.2 mmol) NaCNBH3. After completion of reaction (TCX) for the neutralization reaction add 1 N. NaOH (20 ml) and H2O (200 ml).

The solution is extracted with CH2Cl2(2 x 500 ml), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (4 1). Homogeneous according to TCX fractions are combined and their concentration in vacuo receive in the form of oil net connection. Using HCl solution in MeOH receive HCl-salt. By recrystallization from EtOAc-MeOh obtain 1.27 g (60 title compound in the form of b, H), 4 to 3.5 (m, 7H), 3,83 (s, 3H), 3,37 (s, 1H), 3 2,4 (m, 3H, 2,19 (s, 3H), of 1.34 (s, 3H).

IR (paste): lmax2792, 2707, 2461, 1586, 1490, 1440, 1254 cm-1.

Analysis: C21H25NO5HCl.

Calculated: C 67,102, H 6,972, N 3,727.

Found: C 67,31, H 6,98, N 3,84.

Example 19. ()-7-(Cyclopropylmethyl)-amino-5,6,7,8-tetrahydro-1-naphthalenol, hydrochloride (C-3, scheme C) (compound 19a).

In a round bottom flask of 100 ml equipped with a reflux condenser, download 7,52 ml (43.2 mmol) of diphenylphosphine and THF in a nitrogen atmosphere. To the resulting colorless solution was added 27 ml (43.2 mmol) of n-utility and the red solution is stirred for 10 minutes Then add 2.5 g (10,8 mmol) of ()-N-(cyclopropylmethyl)-1,2,3,4-tetrahydro-8 - methoxy-2-naphtylamine in 10 ml of THF and the mixture is boiled (70oC) 30 hours To stop the reaction, water is added, then extracted with EtOAc (2 x 500 ml + 2 x 250 ml). The combined organic layers washed with brine, dried (MgSO4), filtered and after evaporation in vacuo get the oil that clear liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (4 1 2 1). Homogeneous according to TCX fractions are combined and their concentration in vacuo receive oil. Using HCl solution in VA so pl. 240 244oC.

1H-NMR (MeOH, TMC):(shift 0.17 hours/min) 6,76 (t, 1H), 6.42 per (d, 2H), 3,17 (m, 1H), 2,95 (LW. d, 1H), 2,8 2,12 (m, 6H), 1,45 1,31 (m, 1H).

IR (paste):max3217, 2443, 1591, 1452, 1274 cm-1.

Analysis: C14H19NO HCl.

Calculated: C 66,40, H 7,51, N Of 5.53.

Found: C 65,11, H 7,84, N 5,48,

5,6,7,8-Tetrahydro-7-(2-propenyl)amino-1-naphthalenol, hydrochloride (1.4 g, 67), so pl. 241 242oC. (compound 19b).

IR (paste):max3210, 2960, 2449, 2411 cm-1.

Analysis: C13H17NO HCl.

Calculated: C 65,129, H 7,568, N 5,843.

Found: C 65,28, H To 7.67, N 5,93.

Example 20. ()-7-(Di-2-propylamino)-5,6,7,8 - tetrahydro-1-naphthalenol, hydrochloride (C-3, scheme C) (compound 20).

Synthesized according to the aforementioned method (so pl. 173 175oC).

1H-NMR (CDCl3, TMC): 6,98 (t, 1H), 6,65 (K, 2H), 5,98 - to 5.85 (m, 2H), 5,26 5,12 (m, 4H), 3,3 3,26 (m, 4H), of 3.12 (m, 1H), 2,97 - 2,5 (m, 3H), 2,35 (m, 1H), 2.05 is (m, 1H), and 1.63 (m, 1H).

IR (paste) max3318, 3092, 2955, 1590, 2868, 1466, 1458 cm-1.

Analysis: C16H21NO HCl.

Calculated: C 68,68, H 7,926, N 5,00.

Found: C 68,21, H 8,17, N 5,14.

Example 21. ()-1,2,3,4-Tetrahydro-N-2-(m - trifloromethyl)-2-naphtylamine, hydrochloride (C-2, scheme C) (compound 21a).

To rest the drops are added HOAc. The reaction mixture was stirred for 15 min in an atmosphere of N2and then added 1.26 g (20 mmol) NaCNBH3. At the end according to TCX reaction (24 h) to neutralize the reaction add 1 N. NaOH (20 ml) and H2(200 ml). The solution is extracted with CH2Cl2(3 x 500 ml), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Received a dark yellow oil clear liquid chromatography on 400 ml silica gel 60 (230 to 400 mesh) with elution by the mixture hexane-ethyl acetate (4 1). Homogeneous according TCX fractions are combined and their concentration in vacuo get net connection in the form of oil. Using a solution of HCl in MeOH, get the HCl-salt. By recrystallization from EtOAc-MeOH get 2,71 g (74) the title compound as a white substance so pl. 231 233oC.

1H-NMR (CDCl3, TMC) 7,97 7,94 (m, 2H), 7,69 to 7.59 (m, 2H), 7,16 to 7.09(m, 4H), or 4.31 (s, 2H), 3,37 2,96 (s, 4H), 2,5 (m, 1H).

IR (paste):max2951, 2853, 2784, 2591, 2509, 1597, 1498, 1452, 1376, 1259, 1233 cm-1.

Analysis: C18H18NF3HCl.

Calculated: C 63,25, H Ceiling Of 5.60, N 4,098.

Found: C 63,00, H Of 5.89, N 3,99.

()-1,2,3,4-Tetrahydro-N-benzyl-2-naphtylamine, hydrochloride, white substance, so pl. 244 246oC (compound 21b).

1

IR (paste): max3063, 3045, 2607, 2574, 2505, 2452, 2430, 1591, 1497, 1458, 1355 cm-1.

Analysis: C17H19N HCl.

Calculated: C 74,57, H Of 7.36, N 5,11.

Found: C 74,80, H 7,19, N 5,12.

()-N-(Cyclopropylmethyl)-1,2,3,4-tetrahydro-2-naphtylamine, hydrochloride, white substance, so pl. 231 233oC (connection C).

1H-NMR (CDCl3, TMC): 7,16 to 7.09 (m, 4H), 3,57 of 1.94 (m, 8H), 1,28 of 0.44 (m, 5H).

IR (paste):max1716, 1613, 1596, 1583 cm-1.

Analysis of C14H19N HCl.

Calculated: C 70,72, H 8,68, N Of 5.89.

Found: C 74,63, H Scored 8.38, N 6,04.

()-1,2,3,4-Tetrahydro-N-propyl-2-naphtylamine, hydrochloride, white substance, so pl. 244 246oC.

1H-NMR (CDCl3, TMC): 7,16 7,12 (m, 1H), 3,52 of 1.84 (m, 11H), of 1.05 (t, 3H).

IR (paste):max1609, 1593 cm-1.

Analysis. C13H19N HCl.

Calculated: C 69,16, H 8,93, N 6,20.

Found: C 69,10, Which 9.22 H, N 6,25.

()-1,2,3,4-Tetrahydro-N-propylen-2-naphtylamine, hydrochloride, white substance, so pl. 255 257oC (compound 21d).

1H-NMR (CDCl3, TMC): 7,19 7,06 (m, 4H), 3,98 3,97 (d, 2H), 3.72 points of 1.92 (m, 11H).

IR (paste):max1605, 1587 cm-1.

Analysis. C13H15N HCl.

Calculated: C 70,42, H 7,27, N 6,32.

Non-nuclear submarines. 138 139oC (compound 21e).

1H-NMR (CDCl3, TMC): 7,18 for 7.12 (m, 4H), 6,41 5,46 (m, 6H), 3,81 1,71 (m).

IR (paste):max2426, 1605, 1585 cm-1.

Analysis. C16H21N HCl.

Calculated: C 72,85, H To 8.41, N 5,31.

Found: C 72,76, H 8,49, N Lower Than The 5.37.

()-1,2,3,4-Tetrahydro-N-propenyl-2-naphtylamine, hydrochloride, white substance, so pl. 235 237oC (compound 21f).

1H-NMR (CDCl, TMC): 7,07 (m, 4H), 6 by 5.87 (m, 1H), 6 5, 87 (m, 1H), 5,23 5,07 (K, 2H), 3,36 (d, 2H), 3,02 to 2.57 (m, 5H), to 2.06 (m, 1H), 1,61 (m, 1H), 1,35 (m, 1H).

IR (paste)max2444, 1648, 1609, 1591, 1497, 1462, 1442 and 1424 cm-1.

Analysis: C13H17N HCl.

Calculated: C 69,786, H 8,109, N 6,261.

Found: C 69,82, H 8,11, N 6,32.

Example 22. ()-(Cyclopropylmethyl)-1,2,3,4-tetrahydro-8 - methoxy-2-naphtylamine, white solid (compound 22).

To a solution of 2.64 g (15 mmol) of 8-methoxytyramine, 6 g (60 mmol) of methylcyclopropene HCl and to 4.92 g (60 mmol) of NaOAc in 30 ml of MeOH-THF (1 1) to establish a pH of 4 to 5 added dropwise HOAc. The reaction mixture was stirred for 15 min in an atmosphere of N2after which was added 1.26 g (20 mmol) NaCNBH3. At the end according to the TLC of the reaction (20 h) to neutralize the reaction add 1 N. NaOH (20 ml) and H2O (200 ml). The solution is extracted with CHo
C.

1H-NMR (CDCl3, TMC): 7,11 (t, 1H), 6,67 (K, 2H), of 3.77 (s, 3H), 3,5 3,3 (m, 2H), to 3.02 (m, 2H), 2,89 (m, 3H), 2,58 (m, 1H), 2,1 (m, 1H), 1,67 (s, 3H), 1,4 (m, 1H), 0,74 (m, 2H), 0,5 (m, 2H).

IR (paste):max3076, 2785, 2738, 2433, 1603, 1586, 1472, and 1257 cm-1.

Analysis: C15H21NO HCl.

Calculated: C 67,277, H 8,281, N 5,231.

Found: C 66,94, H 8,43, N 5,24.

Example 23. 1,2,3,4-Tetrahydro-5-methoxy-N, N-bis(2 - methoxymethyl)-2-naphtylamine (C-2, scheme C).

A solution of 1.76 g (10 mmol) of 8-methoxytyramine, 2.66 g (20 mmol) of N,N-bis(2-methoxyethyl)amine and 25 g of p-toluenesulfonic acid is boiled in an atmosphere of N2. To remove the H2O reaction flask equipped with a nozzle Dean-stark. To monitor the reaction using TLC. After 48 h the solvent is removed in vacuum. The crude enamine hydronaut in the presence of 450 mg 10 Pd/C in 50 ml MeOH at 50 psi (3.5 kg/cm2within 24 who (230 400 mesh) by elution with a mixture of hexane-ethyl acetate-isopropanol (10 5 1). Homogeneous according to TLC fractions are combined and their concentration in vacuo obtain 2.3 g (80) of the title compound as a yellow oil.

1H-NMR (CDCl3, TMC):? 7.04 baby mortality of 7.1 (t, 1H), 6,7 6,63 (K, 2H), and 3.8 (s, 3H), 3.43 points (t, 4H), to 3.35 (s, 6H), 3,01 and 2.79 (m, 8H), of 2.38 (m, 1H), 2,02 (m, 1H), 1,64 of 1.55 (m, 1H).

IR (paste):max3000, 2950, 1590 and 1460 cm-1.

Analysis: C17H27NO3.

Calculated: C 69,59, H 9.28 Are, N 4,77.

Found: C 69,64, H 9,14, N 5,34.

Example 24. CIS-()-1,2,3,4-Tetrahydro-1-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 24A) and TRANS-()-1,2,3,4-tetrahydro-1-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 24b) (E-3, scheme E).

To a solution of 9,31 g (50 mmol) of 1,2,3,4-tetrahydro-1-(2-propenyl)-2-oxonation and 20.6 ml (250 mmol) of allylbromide in 60 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 32 ml). The reaction mixture was stirred 30 min, then was added 6.3 g (100 mmol) of laborgerate sodium. The progress of the reaction is controlled by TLC, after stirring the reaction mixture for 24 h at room temperature, neutralized with 20-Noah sodium hydroxide to pH > 13. The solution is extracted with methylene chloride (2 x 1 l), the combined organic salt is washed RA is afia on 800 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (4 1) and selected fractions of 40 ml Homogeneous according to TLC fractions combine their concentration in vacuo obtain 7.9 g (69) a mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (prepared by mixing acetylchloride with methanol (at 0oC) and concentrated in vacuo. The precipitate is recrystallized by dissolving a mixture of ethyl acetate-methanol-concentrated on a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white solid (4.7 g) is a pure CIS-isomer. The mother solution is alkalinized by treatment with saturated sodium bicarbonate to pH > 8 and extracted with methylene chloride. The resulting oil purified liquid chromatography on 800 g of silica gel 60 (230 to 400 mesh) with elution by the mixture hexane-ethyl acetate-methanol (40 10 1) and selected fractions of 40 ml Of fractions 50 61 will receive an additional 1.6 g of pure CIS-isomer of the title compounds after conversion into HCl-salt and precrystallization from a mixture of ethyl acetate-methanol. As a result, the 6.3 g of pure CIS-isomer of the title compound, so pl. 150 151oC.

From fractions 62 84 obtained 1.1 g of an oil, which after conversion into HCl-salt and recrystallization from a mixture of utilize the

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMC): 7.23 percent 7,02 (m, 4H), 5,94 4,96 (m, 3H), 3,53 of 1.6 (m, 13H), of 1.02 (t, J 7 Hz, 3H).

IR (paste):max1641 and 1590 cm-1.

Analysis: C16H23N HCl.

Calculated: C 72,29, H, 9,10, N 5,27.

Found: C 72,09, H 9,16, N, 5,32.

Physical data for the TRANS isomer.

1H-NMR (CDCl3, TMC): 7,15 for 7.12 (m, 4H), 5,69 5,07 (m, 3H), 3,5 of 1.64 (m, 13H), of 0.95 (t, J 7 Hz, 3H).

IR (paste):max1641 and 1592 cm-1.

Analysis: C16H23N HCl.

Calculated: C 72,29, H, 9,10, N 5,27.

Found: C 72,04, H 9,07, N Of 5.29.

CIS-()-1,2,3,4-Tetrahydro-N, 1-di-(2-propenyl)-2-naphtylamine, hydrochloride, white substance, so pl. 138 139oC and TRANS-()-1,2,3,4-tetrahydro-N,1-di(2-propenyl)-n-propyl-2-naphtylamine, hydrochloride, white substance, so pl. 151 153oC.

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMC): 7.23 percent 7,01 (m, 1H), 6,28 to 5.03 (m, 6H), 3,82 of 1.65 (m, 11H).

IR (paste):max1641 and 1589 cm-1.

Analysis: C16H21N HCl.

Calculated: C 72,85, H To 8.41, N 5,31.

Found: C 72,86, H 8,42, N 5,27.

Physical data for the TRANS isomer.

1H-NMR (CDCl3, TMC): 7,17 7,11 (m, 4H), 6,14 5,04 (m, 6H), 3,62 of 1.64 (m, ke: C 72,85, H TO 8.41, N 5,31

Found: C 72,91, H 8,54, N lower than the 5.37

MC: C16H21N

Calculated: 227, 1674

Found: 227, 1660.

TLC (silica gel GF): Rf0.32 in hexane-acetone (4 1).

Example 25. CIS-()-1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 25A) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 25b) (E-3, scheme E).

To a solution of 22 g (0.1 mmol) of 1,2,3,4-tetrahydro-1-(2-propenyl)-8-methoxy-2-oxonation and 32, 8 ml (0.4 mmol) of Propylamine in 400 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 added dropwise HOAc (80 ml). The reaction mixture was stirred 30 min, then added to 12.6 g (0.2 mol) of laborgerate sodium. The progress of the reaction is controlled by TLC. Stirred the reaction mixture for 48 h at room temperature, neutralized by adding 20-th hydrocity sodium to pH > 13. The solution is shaken out etiracetam (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 1 kg of silica gel 60 (230 to 400 mesh) by elution with 4 l of methylene chloride and 3 l of a mixture of methylene chloride-methanol (19 1) and selection of f is) alcohol (product recovery 3b), recrystallized from hexane-ethyl acetate, so pl. 75 76oC.

From fractions 72 112 obtain 15.5 g (60) target mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The obtained solid product is recrystallized by dissolving in a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white matter (14 g) is a pure CIS-isomer of the title compounds (so pl. 199 201oC). The mother solution is alkalinized by treatment with a saturated solution of sodium bicarbonate until pH > 8 and extracted with methylene chloride. The resulting oil purified liquid chromatography on 600 g of silica gel (230 400 mesh) by elution with a mixture of methylene chloride-methanol (20 1) and selected fractions of 40 ml Homogeneous according to TLC fractions are combined and concentrated. The resulting oil is converted into the HCl salt and recrystallization from a mixture of ethyl acetate-hexane obtain 2.6 g of the white matter, which is pure TRANS-isomer of the title compound, so pl. 178 - 180oC.

Physical Dunn who 3H).

IR (paste):max1638, 1586 and 1567 cm-1.

Analysis: C17H25N HCl.

Calculated: C 69,02, H 8,86, N 4,74.

Found: C 69,21, H 8,97, N 4,82.

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMC): 7,27 of 6.68 (m, 3H), 5,32 a 4.86 (m, 3H), 3,81 (s, 3H), 3,62 to 1.82 (m, 13 H) of 0.93 (t, J 7 Hz, 3H).

IR (paste): max1640, 1606 and 1583 cm-1.

Analysis: C12H25N HCl.

Calculated: C 69,02, H 8,86, N 4,74.

Found: C 68,25, H 8,86, N 4,86.

Example 26. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-N,1-di-(2-propenyl)-2-naphtylamine, hydrochloride (compound 26a) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-N,1-di(2-propenyl)-2 - naphtylamine, hydrochloride (compound 26b) (E-3, scheme E).

To a solution of 9 g (40 mmol) of 1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-2-oxonation (crude product obtained by alkylation) and 12 ml (160 mmol) of allylbromide in 160 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 32 ml) the Reaction mixture is stirred for thirty minutes, then add 5 g (80 mmol) of laborgerate sodium.

The progress of the reaction is controlled TCX-analysis. After stirring the reaction mixture for 48 h at room temperature to neutralize add 20-myauth brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 800 g of silica gel (230 400 mesh) by elution with 2 l of methylene chloride and 4 l of methylene chloride (20 1) and selected fractions of 40 ml Of fractions 105 106 gain of 0.42 g (4,8) alcohol. From fractions 107 122 received 8,56 g (83) a mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The resulting residue is recrystallized by dissolving in a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white matter (6,15 g) corresponds to the pure CIS-isomer, so pl. 187 188oC.

The mother solution is alkalinized by treatment with a saturated solution of sodium bicarbonate until pH > 8 and extracted with methylene chloride. The resulting oil purified liquid chromatography on 800 g of silica gel 60 (230 to 400 mesh) with elution by the mixture hexane-ethyl acetate-methanol (20 10 1) and selected fractions of 40 ml Of fractions 57 74 obtained yellow oil, converted into the HCl salt and recrystallized from a mixture of ethyl acetate-hexane. From the definition data for the CIS isomer.

1H-NMR (CDCl3, TMC): 7,16 to 6.67 (m, 4H), 6,72 is 4.93 (m, 6H), and 3.8 (s, 3H), 3,95 of 1.64 (m, 11H).

IR (paste): max1604 and 1585 cm-1.

Analysis: C17H23N HCl.

Calculated: C 39,49, H 8,23, N 4,77.

Found: C 69,41, H Charged 8.52, N 4,79.

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMC): 7,18 of 6.65 (m, 4H), 6,18 to 4.92 (m, 6H), 3,79 (s, 3H), to 3.58 to 1.67 (m, 11H).

IR (paste):max1595 and 1587 cm-1.

Analysis: C17H23N HCl.

Calculated: C 69,49, H 8,23, N 4,77.

Found: C 69,38, H 8,48, N 4,57.

Example 27. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-1-(cyclopropylmethyl)-N-propyl-2-naphtylamine, hydrochloride (compound 27a) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-1- (cyclopropylmethyl)-N-propyl-2-naphtylamine, hydrochloride (compound 27b) (E-3, scheme E).

The solution to 3.52 g (20 mmol) of 1,2,3,4-tetrahydro-1-(cyclopropylmethyl)-2-oxonation and 6.6 ml (80 mmol) of n-Propylamine in 80 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 16 ml). The reaction mixture was stirred 30 min, then add 2.5 g (40 mmol) of laborgerate sodium. The progress of the reaction is controlled TCX-analysis. After stirring the reaction mixture for 48 h at room temperature its neutralise the AOI washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 800 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of methylene chloride-methanol (20 1) and selected fractions of 40 ml

From fractions 44 56 allocated 0.6 g of alcohol. From fractions 57 105 obtained 4.3 g (78 ) a mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The resulting product is recrystallized by dissolving a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white matter (3.2 g) corresponds to the pure CIS-isomer. From the mother liquor by evaporation and recrystallization from a mixture of hexane-acetone receive white matter (0,58 g), which corresponds to the pure TRANS-isomer of the title compounds (so pl. 136 140oC).

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMC): 7,17 of 6.66 (m, 3H), 3,88 of 1.26 (m, 13H), was 1.04 (t, J 7 Hz, 3H), 1,02 0,0 (m, 5H).

IR (paste):max1600 and 1585 cm-1.

Analysis: C18H27NO HCl.

Calculated: C 69,77, H 9,11, N 4, (CDCl3, TMC): 7,27 of 6.66 (m, 3H), 3,79 (s, 3H), 3,92 1,3 (m, 13H), of 0.95 (t, J 7 Hz, 3H), 0,8 0,0 (m, 5H).

IR (paste):max1601 and 1587 cm-1.

Analysis: C18H27NO HCl.

Calculated: C 69,77, H 9,11, N To 4.52.

Found: C 69,45, H 9,17, N 4,62

Example 28. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-1-(cyclopropylmethyl)-(2-propenyl)-2-naphtylamine, hydrochloride (compound 28a) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-1- (cyclopropylmethyl)-N-(2-propenyl)-2-naphtylamine, hydrochloride (compound 28b) (E-3, scheme E).

The solution to 3.52 g (20 mmol) of 1,2,3,4-tetrahydro-1-(cyclopropylmethyl)-8-methoxy-2-oxonation and 6 ml (80 mmol) of allylamine in 80 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 16 ml). The reaction mixture was stirred 30 min, then add 2.5 g (40 mmol) of laborgerate sodium. The progress of the reaction is controlled TCX-analysis. After stirring the reaction mixture for 48 h at room temperature, it is neutralized by adding 20-Noah sodium hydroxide to pH >13. The solution is extracted with ethyl acetate (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 800 g of silica gel 60 (230 to 400 mesh) with suirou the mixtures of CIS - and TRANS-isomer as a yellow oil. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The resulting product is recrystallized by dissolving in a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white matter (3,35 g) corresponds to the pure CIS-isomer of the title compound, so pl. 214 215oC. Concentration of the mother liquor in vacuo and recrystallization from a mixture of hexane-ethyl acetate obtained (0.8 g) of the white matter, which corresponds to the pure TRANS-isomer of the title compound, so pl. 146 148oC.

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMC): 7,18 only 6.64 (m, 3H), 6,3 5,41 (m, 3H), of 3.78 (m, 3H), 3,98 of 1.24 (m, 11H), 0,92 0,0 (m, 5H).

IR (paste):max1600 and 1585 cm-1.

Analysis: C18H25NO HCl.

Calculated: C 70,23, H 8,51, N 4,55.

Found: C 70,23, H To 8.70, N 4,59.

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMC): 7,26 to 7.09 (m, 3H), 6.73 x 5,46 (m, 3H), 3,79 (s, 3H), 3,92 1,22 (m, 11), 0,92 0,0 (m, 5H).

IR (paste):max1604 and 1585 cm-1.

Analysis: EP 29. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-N,1-di-(cyclopropylmethyl)-2-naphtylamine, hydrochloride (compound 29a) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-N,1-di-(cyclopropylmethyl)-2-naphtylamine, hydrochloride (compound 29b) (E-3, scheme E).

The solution to 3.52 g (20 mmol) of 1,2,3,4-tetrahydro-1-(cyclopropylmethyl)-8-methoxy-2-oxonation and 8.6 g (80 mmol) of the hydrochloride of cyclopropanemethylamine and 6.6 g (80 mmol) of monohydride sodium acetate in 100 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 16 ml). The reaction mixture was stirred 30 min, then add of 2.51 g (40 mmol) of laborgerate sodium. The progress of the reaction is controlled TCX-analysis. After stirring the reaction mixture for four days at room temperature, neutralize its 20-Noah sodium hydroxide to pH >13 with subsequent removal in vacuum THF-MeOH. The concentrate is treated with 600 ml of ethyl acetate, the organic layers extracted with 3 N. hydrochloric acid (2 x 100 ml), with translation in the organic compounds of the main character in the water layer remaining in the organic layer of neutral and acidic compounds. After drying the organic layer over anhydrous Clifton sodium, it is alkalinized by adding 20-Noah of sodium hydroxide and extra is aslo clear liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (4 1) and selected fractions of 40 ml Of fractions 32 70 allocated 4.3 g (40) mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The resulting product is recrystallized by dissolving in a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (at 20oC). Selected white matter (1.63 g) corresponds to the pure CIS-isomer of the title compound, so pl. 218 219oC.

The mother solution is alkalinized by treatment with a saturated solution of sodium bicarbonate until pH > 8 and extracted with methylene chloride. The resulting oil purified liquid chromatography on 400 ml of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (4 1) and selected fractions of 40 ml Homogeneous according to TCX fractions are combined and their concentration receives a yellow oil, which after conversion to the HCl salt and recrystallization from ethyl acetate-hexane obtain 0.45 g of pure transisomer the title compound as a white substance so pl. 149 150oC.

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMC): 7,27 of 6.66 (m, 3H), and 3.8 (s, 3H), 3,8 HCl.

Calculated: C 70,90, H 8,77, N 4,35.

Found: C To $ 70.88, H 8,92, N To 4.52.

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMC): 7,26 to 6.67 (m, 3H), and 3.8 (s, 3H), 4,1 to 1.28 (m, 11H), 0,82 0,0 (m, 10H).

IR (paste): max1602 and 1591 cm-1.

Analysis: C19H27NO HCl.

Calculated: C 70,90, H 8,77, N 4,35.

Found: C 70,66, H 8,64, N 5,03.

Example 30. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-1-(2-propenyl)-N-cyclopropylmethyl-2-naphtylamine, hydrochloride (compound 30a) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-1- (2-propenyl)-N-cyclopropylmethyl-2-naphtylamine, hydrochloride (compound 30b) (E-3, scheme E).

To a solution of 2.6 g (12 mmol) of 1,2,3,4-tetrahydro-1-(2-propenyl)-2-oxo-8-methoxynaphthalene, 5,16 g (48 mmol) of the hydrochloride of cyclopropanemethylamine and 3.9 g (48 mmol) of the monohydrate of sodium acetate in 60 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 9.6 ml). The reaction mixture was stirred 30 min, then added 1.5 g (24 mmol) of laborgerate sodium. The progress of the reaction is controlled TCX-analysis.

After stirring the reaction mixture for four days at room temperature, neutralize its 20-Noah sodium hydroxide to pH > 13 with subsequent removal in vacuum THF-MeOH.Tata organic compounds main character in the water layer remaining in the organic layer of neutral and acidic compounds. After drying the organic layer over anhydrous magnesium sulfate and concentration in vacuo allocate 0.84 g (32) of alcohol. The aqueous layer containing the target compound, alkalinized 20-Noah sodium hydroxide and extracted with ethyl acetate (2 600 ml). The combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (4 1) and selected fractions of 40 ml

From fractions 35 70 selected 1 g of a mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The resulting product is recrystallized by dissolving in a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white matter (0,67 g) corresponds to the pure CIS-isomer of the title compound, so pl. 186 187oC.

The mother solution is alkalinized by treatment with a saturated solution of sodium bicarbonate until pH > 8 and extracted with methylene chloride. The obtained oil or fractions of 40 ml From fractions 30 70 after transformation into NCl-salt and recrystallization from ethyl acetate-hexane obtain 0.2 g of pure TRANS-isomer of the title compound as a white substance so pl. 185 186oC.

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMS): 7,26 to 6.67 (m, 3H), 5,96 to 4.92 (m, 3H),3,8(s, 3H), 3,78 of 1.29 (m, 11H), 0,72 0,42 (m, 5H).

IR (paste):max1600 and 1584 cm-1.

Analysis: C18H25NOHCl.

Calculated: C 70,23, H 8,51, N 4,55.

Found: C 69,99, H 8,63, With 4.64 N.

Physical data for the TRANS-isomer.

1H-NMR(CDCl3, TMS): 7,26 of 6.66 (m, 3H), 6,02 to 4.92 (m, 3H), and 3.8 (s, 3H), 3,92 of 1.28 (m, 11H), 0,78 0,42 (m, 5H).

IR (paste):max1639 and 1595 cm-1.

Analysis: C18H25NO NCl.

Calculated: C 70,23, H 8,51, N 4,55.

Found: C 69,91, H To 8.57, N Br4.61.

Example 31. CIS-()-1,2,3,4-Tetrahydro-5-methoxy-1-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 31A) and TRANS-()-1,2,3,4-tetrahydro-5-methoxy-1-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 31b) (E-3, scheme E).

To a solution of 0.97 g (15 mmol) of 1,2,3,4 - tetrahydro-1-(2-propenyl)-5-methoxy-2-oxonation and 1.8 ml (to 22.5 mmol) of n-Propylamine in 8 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0-5oC to establish a pH of 4 to 5 pinboliada sodium. The progress of the reaction is controlled TLC-analysis. After stirring the reaction mixture for 18 h at room temperature, neutralize its 20-Noah sodium hydroxide to pH >13. The solution is extracted with methylene chloride (2 x 1 l), the organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) with elution by the mixture hexane-ethyl acetate-methanol (40 10 1) and selected fractions of 40 ml Of fractions 32 46 emit 0.9 g (78) light yellow oil, treated with excess anhydrous hydrogen chloride in methanol and concentrated in vacuum. By recrystallization of the resulting product from ethyl acetate-methanol to obtain 0.75 g of a pale yellow substance so pl. 183 184oC, which corresponds to cisisomer the title compound. From fractions 44 47 receive 0.1 g of light yellow oil, is also converted into the hydrochloride by the above method. By recrystallization from a mixture of ethyl acetate-hexane get white substance so pl. 197 198oC, which corresponds to the TRANS-isomer of the title compound.

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMS): 7,12 of 6.65 (m, 3H), of 5.89 5,02(m, 3H), 3,82 (s, 3H), 3,4 1,7(m, 13H), of 1.02 (t, J 7 Gino: 259, 1936

Found: 259, 1959.

Analysis: C17H25NO HCl.

Calculated: C 69,02, H 8,86, N 4,74.

Found: C 68,64, H 9,01, N 4,62.

TLC (silica gel GF): Rf0,34 hexane-ethyl acetate-methanol (40 10 1)

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMS): 7,14 of 6.68 (m, 3H), 5,78 5,04 (m, 3H), 3,81 (s, 3H), 3,52 of 1.54 (m, 13H), of 0.95 (t, J 7 Hz, 5H).

IR (paste): max1641 and 1588 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,02, H 8,86, N 4,74.

Found: C 70,38, H 8,93, N 4,12.

Example 32. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-1-(2-propylamino)-1-natalymartynova acid, methyl ester (compound 32A) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-2-(2-propylamino)-1-natalymartynova acid, methyl ester (compound 32b) (G-2, circuit (G).

To a solution of 18,74 g (0.08 mmol) of 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-naphthaleneboronic acid in the form of methyl ester and 30 ml (0.4 mmol) of allylamine in 320 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 added dropwise HOAc (50 ml). The reaction mixture was stirred 30 min, then add 10 g (0.16 mol) of laborgerate sodium. The progress of the reaction is controlled TLC-analysis. After stirring the reaction mixture for three d is t to use sodium hydroxide, because it will result in hydrolysis of the methyl ester of a strong base). The solution is extracted with methylene chloride (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 1 kg of silica gel 60 (230 to 400 mesh) with elution by the mixture hexane-ethyl acetate (2 1) and selected fractions of 40 ml

From fractions 98 106 allocated to 4.2 g (19) light yellow oil, which corresponds to the TRANS-isomer in the form of free base.

From fractions 107 139 obtained 14.3 g (65) light yellow, which corresponds to the CIS-configuration. Both oils are converted to HCl salt by treatment with an excess of anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo.

The predominant CIS-isomer recrystallized from a mixture of ethyl acetate: methanol in the white matter of the so pl. 223 225oC. Recrystallization resulting in a smaller amount of TRANS-isomer of ethyl acetate-hexane get white substance so pl. 170 173oC.

Physical data for the CIS isomer.

1H-NMR(CDCl3, TMS): 7,25 to 6.78 (m, 3H), 6,01 the 5.51 (m, 3H), 3,81(s, 3H), 3,71 (C, 13H), 4,46 to 1.82 (m, 9H).

Found: C 61,98, H 7,34, N 4,73.

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMS): 7,26 6,85 (m, 3H), 6,01 the 5.51 (m, 3H), 3,81 (s, 3H), 3,71 (s, 3H), 4,23 2,02 (m, 9H).

IR (paste):max1735, 1632, 1592 and 1574 cm-1.

Analysis: C16H21NO3HCl.

Calculated: C 61,63, H 7,11, N 4,49.

Found: C 61,47, H 7,29, N 4,56.

Example 33. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-3-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 33a) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-3-(2-propenyl)-N-propyl-2-naphtylamine, hydrochloride (compound 33b) (F-5, scheme F).

To a solution of 3 g (14 mmol)of 1,2,3,4-tetrahydro-8-methoxy-3-(2-propenyl)-2-oxonation and 4.6 ml (56 mmol) of n-Propylamine in 70 ml of MeOH-THF (1 1) in a nitrogen atmosphere at 0 to 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 11 ml).

The reaction mixture was stirred 30 min, then add 1.8 g (28 mmol) of laborgerate sodium. The progress of the reaction is controlled TLC-analyte. After stirring the reaction mixture for 24 h at room temperature, neutralize its 20-Noah sodium hydroxide to pH > 13. The solution is extracted with methylene chloride (2 x 1 l), the combined organic layers washed with brine, dried (MgSO4), filtered and lirovanie 1 l 10-s and 2 l of 25-aqueous acetone in methylene chloride.

Of fractions 21 70 receive 2,87 g (79) a mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The resulting product is recrystallized by dissolving in a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white matter (2.4 g) corresponds to the CIS-configuration.

The mother solution is alkalinized by treatment with a saturated solution of sodium bicarbonate until pH > 8, followed by extraction of methylene chloride. The resulting oil purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of methylene-acetone (3 1) and selected fractions of 40 ml

From fractions 24 31 additionally obtained 0.14 g of pure product after conversion to the HCl salt and recrystallization from ethyl acetate-methanol. The final result of 2.38 g of pure CIS-isomer of the title compound, so pl. 216 - 219oC.

From fractions 33 72 is obtained 0.4 g of the oil from which received of 0.38 g of pure TRANS-isomer of the title compounds after conversion into HCl-salt and recrystallization from atilas the>H-NMR (CDCl3, TMS): 7,27 of 6.5(m, 3H), of 5.92 of 4.95 (m, 3H), of 3.78( s, 3H), 3,54 of 1.55 (m, 13H), of 1.02 (t, J 7 Hz, 3H).

IR (paste):max1604 and 1587 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,02, H 8,86, N 4,74.

Found: C 68,97, H 8,91, N 4,92.

Physical data for the TRANS isomer:

1H-NMR(CDCl3, TMS): 7,26 of 6.65 (m, 3H), 5,88 of 5.06 (m, 3H), of 3.78 (s, 3H), 3,38 of 1.6 (m, 13 H), 0,99 (t, J 7 Hz, 3H).

IR (paste):max1605 and 1593 cm-1.

Analysis: C17H25NO HCl.

Calculated: C 69,02, H 8,86, N 4,74.

Found: C 63,73, H 9,12, N 4,94.

Example 34. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-N,3-di-(2-propenyl)-2-naphtylamine, hydrochloride (compound 34a) and TRANS-()-1,2,3,4-tetrahydro-8-methoxy-N,3-di-(2-propenyl)-2-naphtylamine, hydrochloride (compound 34b) (F-5, scheme F).

To a solution 3,24 g (15 mmol) of 1,2,3,4-tetrahydro-8-methoxy-2-oxo-3-(2-propenyl)naphthalene and 4.5 ml(60 mmol) of allylamine in 75 ml of MeOH-THF (1 1) in nitrogen atmosphere at 0, 5oC to establish a pH of 4 to 5 dropwise added HOAc (about 12 ml). The reaction mixture was stirred 30 min, then added to 1.9 g (30 mmol) of laborgerate sodium. The progress of the reaction is controlled TLC-analysis. After stirring the reaction mixture for 24 h at room temperature, neutralize its 20-n is Lois washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil purified liquid chromatography on 40 g of silica gel 60 (230 to 400 mesh) by elution with 2 l of 10-s and 1 l of 25-aqueous methylene chloride in acetone and sampling fractions in 40 ml.

From fractions 14 56 received 3.3 grams (86,3) mixture of CIS - and TRANS-isomer. The mixture is treated with excess anhydrous hydrogen chloride in methanol (obtained by mixing at 0oC acetylchloride with methanol) and concentrated in vacuo. The resulting product is recrystallized by dissolving in a mixture of ethyl acetate-methanol, the concentration in a water bath prior to the appearance of crystals and curing the mixture in the refrigerator (-20oC). Selected white matter (2,74 g) corresponds to the pure CIS-isomer of the title compound.

The mother solution is alkalinized by treatment with a saturated solution of sodium bicarbonate until pH > 8, followed by extraction of methylene chloride. The resulting oil purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of methylene acetone and sampling fractions in 40 ml.

From fractions 20 22 additionally obtained 0.11 g of pure CIS-isomer after conversion into HCl-salt and recrystallization from ethyl acetate-methanol 23 43 received 0,48 g butter, which receive and 0.46 g of pure TRANS-isomer of the title compounds, which are a white substance so pl. 123 125oC after conversion into HCl-salt and recrystallization from ethyl acetate-hexane.

Physical data for the CIS isomer.

1H-NMR (CDCl3, TMS): 7,13 of 6.65 (m, 3H), 6,3 of 4.95 (m, 6H), of 3.78 (s, 3H), 3.96 points of 1.88 (m, 11H).

IR (paste):max1640 and 1587 cm-1.

Analysis: C17H23NO HCl.

Calculated: C 69,49, H 8,23, H 4,77.

Found: C 69,75, H 8,48, N 4,82.

Physical data for the TRANS-isomer.

1H-NMR (CDCl3, TMS): 7,14 only 6.64 (m, 3H), 6.22 per 4,95, (m, 6H), 7,79 (s, 3H), 3,82 of 1.6 (m, 11H).

IR (paste):max1602, 1592 1582 and-1.

Analysis: C17H23NO HCl.

Calculated: C 69,49, H 8,23, N 4,77.

Found: C 69,86, H 8,43, N 4,81.

Example 35. CIS-()-5,6,7,8-Tetrahydro-8-(2-propenyl)-7-(2-propylamino)-1-naphthalenol, hydrochloride (compound 35A) and ()-2,3,3 a,4,5,9 b-hexahydro-2-methyl-3-(2-propenyl)(1H)benzo(e)indol-9-ol, hydrochloride (compound 35b) (E-4, scheme E).

In a three-neck flask, equipped with a fridge and tube, under nitrogen atmosphere at 0oC is treated with a solution of 1 ml (6 mmol) of diphenylphosphine in 12 ml of THF and 4.4 ml (6 mmol) n-utility (a 1.6 M in hexane). A mixture of si-N, 1-di-(2-propenyl)-2-naphtylamine in 12 ml THF. Red color solution is boiled (bath temperature 70oC) 48 hours the Reaction mixture is neutralized with water and extracted with ethyl acetate (2 x 500 ml). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo get the oil that clear liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution 1 l 10-s and 3 l 33-aqueous acetone in hexane and sampling fractions in 40 ml.

From fractions 31 50 obtained 0.32 g (44) of free base of TRANS-()-2,3,3 a,4,5,9 b-hexahydro-2-methyl-3-(2-propenyl)-1H-benzo(e)indole chloride as a pale yellow oil. The oil is treated with excess anhydrous hydrogen chloride in methanol and concentrated in vacuo. By recrystallization from a mixture of ethyl acetate-methanol to obtain pure TRANS-()-2,3,3 a,4,5,9 b-hexahydro-2-methyl-3-(2-propenyl)(1H)benzo(e)indol-9-ol, hydrochloride as a white substance so pl. 257 258oC.

From fractions 68 100 allocated 0.25 g (34) of the free base of the CIS isomer of the title compound as a pale yellow oil. The oil obtained by the above method is transferred to the HCl salt and recrystallization from ethyl acetate-methanol to obtain pure CIS-()-5,6,7,8-tetrahydro-8-(2-propenyl)-7-(2-propenyl 1H-NMR (CDCl3, TMS): 7 to 6.6 (m, 3H), 6,13 5,61 (m, 3H), 4,03 to 1.5 (m, 11H), 1,5 1,48 (d, 3H).

IR (paste):max1606 and 1584 cm-1.

Analysis: C16H21NO HCl.

Calculated: C 68,68, H Of 7.93, N 5,01.

Found: C 68,64, H 8,25, N 5,51.

Physical data for the CIS isomer.

1H-NMR (CDCl3, MA): 7 6 (m, 3H), 6,03 of 5.5 (m, 6H), 3,83 of 1.6 (m, 11H).

IR (paste):max1610 and 1587 cm-1.

Analysis: C16H21NO HCl.

Calculated: C 68,68, H Of 7.93, N 5,01.

Found: C 68,64, H 8,07, N 4,98.

Example 36. CIS-()-5,6,7,8-Tetrahydro-8-(2-propenyl)-7-(2-propylamino)-1-naphthalenol, hydrochloride (compound 36) (E-4, scheme E).

In a three-neck flask, equipped with a fridge and tube, under nitrogen atmosphere at 0oC solution of 2.8 ml (16 mmol) of diphenylphosphine in 16 ml of THF is treated with 10 ml (16 mmol) of n-utility (a 1.6 M in hexane). The mixture is stirred for 10 min at room temperature, then add 1 g (4 mmol) of CIS-()-1,2,3,4-tetrahydro-8-metoki-1-(2-propenyl)-N-propyl-2-naphtylamine in 16 ml of THF. The obtained red solution is boiled (bath temperature 70oC) 48 hours Then the reaction mixture is neutralized with water and extracted with ethyl acetate (2 x 500 ml). The organic layer was washed with brine, dried (MgSO4), Phil 800 g of silica gel 60 (230 to 400 mesh) by elution with 2 l of 10-s and 3 l 20-aqueous acetone in hexane and sampling fractions in 40 ml.

From fractions 88 115 obtained 0.85 grams (87) of free base as a pale yellow oil. The oil is treated with excess anhydrous hydrogen chloride in methanol and concentrated in vacuo. By recrystallization from a mixture of ethyl acetate-methanol to obtain the pure title compound as a white substance so pl. 162 164oC.

1H-NMR (CDCl3, TMS): 7 6,59 (m, 3H), 6 of 4.9 (m, 3H), of 3.73 of 1.73 (m, 13H), of 1.05 (t, J 7 HZ, 3H).

IR (paste):max3405, 1610 and 1588 cm-1.

Analysis: C16H23NO HCl.

Calculated: C 68,19, H 8,58, N Equal To 4.97.

Found: C 67,85, H 8,86, N 4,87.

Example 37. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-1-(2-propylene)-N-2-propyl-2-naphthaleneacetic (compound 37).

A solution of 3.5 g (13.5 mmol) of CIS-()-1,2,3,4-tetrahydro-8-methoxy-1-(2-propylene)-N-2-propyl-2-naphtylamine in the form of a free base, 10 ml of acetic anhydride, 10 ml of pyridine and 13.5 ml of methylene chloride is stirred for 4 h at room temperature. Then the reaction mixture was diluted with 10 ml of methanol, stirred for 30 min, then add 10 ml of water. The mixture is extracted with methylene chloride (2 x 500 ml) the organic layer was washed with 10% aqueous sodium bisulfate, brine, 1 N. sodium hydroxide, dried (MgSO4), filter and concentrate in what Finance with a mixture of methylene chloride-acetone (9 1) and selected fractions of 40 ml

From fractions 24 42 received 3.75 g (92) of pure title compound as a colourless oil.

1H-NMR (CDCl3, TMS): 7,1 6,63 (m, 3H), 5,8 a 4.83 (m, 3H), 4,06 to 3.92 (m, 1H), 3,8 3,76 (s, 3H), 3,85 of 1.24 (m, 11H), 2,14 2,1 (s, 3H), 0,92 0,9 (s, 3H).

IR (paste):max1643 and 1586 cm-1.

MA: M+301, other ions at m/z 260, 218, 200, 185, 169, 159, 145, 126.

Analysis: C19H27NO2.

Calculated: C 75,71, H 9,03, N 4,65.

Found: C 75,21, H Of 9.30, N With 4.64.

Example 38. CIS-()-1,2,3,4-Tetrahydro-8-metoki-N,1-dipropyl-2-naphtylamine, hydrochloride (compound 38) (E-3, scheme E).

The mixture 2,95 g (10 mmol) of CIS-()1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N-propyl-2-naphtylamine, 0.3 g 10 palladium on coal and 100 ml of methanol is shaken in a Parr apparatus for hydrogenation under pressure of 40 psi (2.8 kg/cm2within 2 hours TLC-analysis revealed the absence of the original products. The mixture is filtered through a layer of zeolite and contact vacuum. By recrystallization of the resulting residue from a mixture of ethyl acetate: methanol receive 2,74 g (92) of the title compound as a white substance so pl. 249 250oC.

1H-NMR (CDCl3, TMS): 7,16 of 6.73 (m, 3H), 3,68 3,55 (m, 1H), 3,38 1,2 (m, 14H), 1,04 0,93 (t, J 7 Hz, 6H).

IR (paste): max1601 and 1584 cm-1.

Example 39. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-1-(2-propenyl)-N,N-dipropyl-2-naphtylamine, hydrochloride (compound 39) (E-3, scheme E).

In a round bottom flask, equipped with a trap Dean-stark water load 7,05 g (40 mmol) of 8-methoxy-1-(2-propenyl)-2-tetralone, 11 ml (80 mmol) of dipropylamine, 76 mg of the monohydrate of p-toluenesulfonic acid and 100 ml of toluene and heated in a nitrogen atmosphere. After 24 hours add 11 ml of dipropylamine and boiling continued for another 24 hours Away aliquot number, which concentrate and analyze using1H-NMR in the presence of hydrogen peak of the enamine. According to the analysis, the reaction was held at 85 the mixture is Then concentrated in vacuo. The concentrate is dissolved in 100 ml of THF and 13.8 ml (160 mmol) of allylbromide and the mixture is boiled for 48 hours After removal of the solvent in vacuum1H-NMR analysis revealed the absence of the enamine. The crude product is dissolved in 160 ml of a mixture of 2-propanol-THF (1 1) and in nitrogen atmosphere add 5 ml of acetic acid. The mixture is treated of 5.03 g (80 mmol) of laborgerate sodium and stirred for 48 h at room temperature. Then the reaction mixture was added 50 ml of water, stirred for 30 min, alkalinized with a saturated solution of sodium bicarbonate and extracted with methylene chloride. Organic slodostnoe chromatography with 560 g of silica gel 60 (230 to 400 mesh) by elution 10 ethyl acetate in hexane with the addition (0.5 triethylamine) and selected fractions of 40 ml

Fractions 22 53 are combined and concentrated in vacuo. The obtained brown oil re-cleaned in the same column but with elution at this time 2 liters of methylene chloride and 4 l of a mixture of methylene chloride-methanol (20 1) and selected fractions of 40 ml

From fractions 64 115 received 2,96 (24,5) of target compound as a yellow oil. The oil obtained is treated with excess anhydrous hydrogen chloride in methanol and concentrated in vacuo. By recrystallization from ethyl acetate-methanol to obtain 2.14 g of pure title compound as a white substance so pl. 159 160oC.

1H-NMR (CDCl3, TMS): 7,18 6,74 (m, 3H), 5,78 489 (m, 3H), and 3.8 (s, 3H), to 3.58 of 1.74 (m, 16H), of 1.05 (t, J 7 Hz, 6H). Experiments on the splitting yielded a value for the constant splitting of the protons of C-1 and C-2, equal to or 4.31, which indicates that diequatorial protons, i.e., that the product is CIS-compound.

IR (paste):max1640 and 1586 cm-1.

Analysis: C20H31NO HCl.

Calculated: C 71,09, Of 9.55 N, N 4,15.

Found: C 71,03, H 9,79, N 4,23.

Example 40. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-N,N,1-tripropyl-2-naphtylamine, hydrochloride (compound 40).

The solution to 1.79 g (6 mmol) of the hydrochloride of the CIS-()-1,2,3,4 - tetrahydro-8-methoxy-N, 1-dipropyl-2-at the room temperature in nitrogen atmosphere. After 24 h, TLC-analysis revealed the absence of the original products. The reaction mixture was neutralized with 4 ml of methanol and stirred for 1 h Then the mixture is treated with water followed by a 20-s of sodium hydroxide to pH > 7 8 and extracted with ethyl acetate. The organic layer is washed with water, 10% sodium bisulfate, saturated sodium bicarbonate solution, brine, dried (MgSO4), filtered and concentrated in vacuo. The obtained brown oil purified liquid chromatography with 560 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (9 1) and selected fractions of 40 ml

From fractions 38 70 obtained 1.8 g of yellow oil which is dissolved in 96 ml of THF and treated 0,91 g (24 mmol) of socialogical (alpha) in nitrogen atmosphere. The resulting mixture was boiled for 5 h, cooled to room temperature, diluted with 200 ml of THF and transferred to an Erlenmeyer flask equipped with a magnetic stirrer, which is added dropwise a saturated solution of sodium sulfate to destroy excess lydialydia. After the grey suspension becomes white mixture, diluted with ethyl acetate (800 ml) and dried over anhydrous magnesium sulfate. Filtration and concentration get a light yellow oil, which cleans II 40 ml.

From fractions 41 48 obtained 1.27 g (70) free base 12 in the form of almost colorless oil. Approximately 0.5 g of the obtained product by treatment with HCl in methanol and recrystallization from a mixture of ethyl acetate-hexane transferred to the hydrochloride of the title compound, representing white matter so pl. 152 154oC.

1H-NMR (CDCl3, TMS): 7,15 of 6.7 (m, 3H), 3,81 (s, 3H), 3,78 of 1.24 (m, 18H), 1,06 0,99/0,94 (3T, J 7 Hz, 9H).

IR (paste):max1599 and 1588 cm-1.

Analysis: C20H33NO HCl.

Calculated: C 70,66, H 10,08, N 4,12.

Found: C 70,44, H 10,22, N 4,32.

Example 41. CIS-()-5,6,7,8-tetrahydro-8-propyl-7-(propylamino)-1-naphthalenol, hydrochloride (compound 41) (E-4, scheme E).

A solution of 0.57 g (2 mmol) of CIS-()-1,2,3,4-tetrahydro-8-methoxy-N,1-dipropyltryptamine, hydrochloride in 10 ml of 48-Noah Hydrobromic acid is boiled (bath temperature 120oC) 8 hours TLC-analysis showed the absence of starting compounds. The mixture is cooled to room temperature, treated with 20-Noah sodium hydroxide to pH > 7 8 and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The oil obtained by the action of an excess of anhydrous hydrogen chloride is a white substance so pl. 244 245oC.

1H-NMR (CDCl3, TMS): 6,98 6,59 (m, 3H), 3,63 of 1.36 (m, 14H), 1,05 0,91 (2T, J 7 Hz, 6H).

IR (paste):max3226, 1609 and 1586 cm-1.

Analysis: C16H26NO HCl.

Calculated: C 67,71, H 9,23, N 4,94.

Found: C 67,52, H 8,82, N 5,50.

CIS-()-5,6,7,8-tetrahydro-7-(dipropylamino)-8-propyl-1-naphthalenol, hydrochloride, white substance, so pl. 237 239oC.

1H-NMR (CDCl3, TMS): 7,01 of 6.61 (m, 3H), 3,82 1,22 (m, 19H), of 1.03 (2T, J 7 Hz, 6H), of 0.93 (t, J 7 Hz, 3H).

IR (paste):max3400, 1607 and 1591 cm-1.

Analysis: C19H31NO.

Calculated: C 70,02, H 9,90, N 4,30.

Found: C 69,99, H 10,14, N 4,39.

Example 42. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-2-(2-propylamino)-1-naphthalenemethanol, hydrochloride (compound 42) (4 G, the diagram G).

A solution of 4.13 g (15 mmol) of methyl ester of CIS-()- 1,2,3,4-Tetrahydro-8-methoxy-2-(2-propylamino)-1 - naphthaleneboronic acid in 30 ml of THF, cooled to 0 5oC, in nitrogen atmosphere is treated to 1.14 g (30 mmol) of socialogical. After stirring the mixture for 24 h at room temperature TLC-analysis showed the absence of starting solution of sodium sulfate before turning grey suspension in white. To the resulting mixture dobavlyayu the mixture is filtered through a layer of zeolite and concentrated in vacuo. The crude product was then purified liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution 1 l 25-s and 2 l 50-aqueous acetone in hexane and sampling fractions in 40 ml.

From fractions 42 95 get 3,22 g (87 target alcohol. Treatment with excess HCl in MeOH and recrystallization from ethyl acetate-methanol obtain 2.24 g of pure title compound as a white substance so pl. 203 204oC.

1H-NMR (CDCl3, TMC): 7,2 of 6.65 (m, 3H), 6,3 5,38 (m, 3H), of 3.84 (s, 3H), 4,12 2,1 (m, 12H).

IR (paste):max3220, 1645, 1608 and 1585 cm-1.

Analysis: C15H21NO2HCl.

Calculated: C 63,48, H 7,81, N 4,94.

Found: C 63,14, H A 7.92, N 4,95.

TRANS-()-1,2,3,4-tetrahydro-8-methoxy-2-(2-propylamino)-1-naphthalenol, hydrochloride, white substance, so pl. 161 162oC.

1H-NMR (CDCl3, TMC): 7,18 6,62 (m, 3H), 6,24 5,42 (m, 3H), of 3.75 (s, 3H), of 4.38 of 1.9 (m, 12H).

IR (paste):max3370, 1649, 1603 and 1594 cm-1.

Analysis: C15H21NO2HCl.

Calculated: C 63,48, H 7,81, N 4,94.

Found: C, 63.47 Per, H A 7.92, N Is 5.06.

Example 43. CIS-()-1,2,3,4-Tetrahydro-8-methoxy-2-propylamino-1-naphthalenol, hydrochloride (compound 43).

A mixture of 0.99 g (4 mmol) of the hydrochloride of the CIS-()-1,2,3,4-tetrahydro-8-methoxy-2-(2-Propiedad 50 psi (3.5 kg/cm2). After 18 h the mixture is filtered through a layer of zeolite and concentrated in vacuo. Processing the obtained oil with excess HCl in MeOH, followed by recrystallization from ethyl acetate-methanol to obtain the pure title compound as a white substance so pl. 233 234oC.

1H-NMR (CDCl3TMC): 7,17 to 6.67 (m, 3H), 3,83 (s, 3H), 4,14 of 1.9 (m, 14H), of 1.05 (t, J 7 Hz, 3H).

IR (paste): lambda max 3308, 1602, 1585, and 1561 cm-1.

Analysis: C15H23NO2HCl.

Calculated: C 63,04, H Of 8.47, N 4,9.

Found: C 63,05, H 8,54, N 4,9.

Example 44. ()-1,2,3,4-Tetrahydro-8-methoxy-1-methylene-2-(2-propenyl)-2-propylaminoethyl, hydrochloride (compound 44).

1,2,3,4-Tetrahydro-8-methoxy-1-hydroxymethyl-2-(2-propenyl)-N-propylnitrosamine dissolved in a solution containing 2 ml of pyridine and 4 ml of methylene chloride, treated 0,76 g (4 mmol) of p-toluensulfonate and the resulting mixture was stirred for 24 h Then the mixture is neutralized with 2 ml of saturated sodium bicarbonate solution and then with 2 ml of methanol. After stirring the mixture for 1 h, the solution is extracted with methylene chloride (2 x 300 ml). The organic layer is washed with water, saturated sodium bicarbonate solution, brine, dried (MgSO4), filtered and after koncentrirane is the formation of a mixture of hexane-acetone (4 1) and selected fractions of 40 ml

From fractions 15 22 gain of 0.53 g of light yellow oil, which according to the1H-NMR responds structure tosilata. The oil obtained is dissolved in 4 ml of THF, treated with 2 ml (2 mmol) of tert-butoxy potassium (1 M in THF) and boiled for 2 h the resulting mixture was treated with brine and extracted with methylene chloride (2 x 300 ml). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Concentrate clear liquid chromatography on 400 g of silica gel 60 (230 to 400 mesh) by elution with a mixture of hexane-acetone (9 1) and selected fractions of 40 ml

From fractions 13 18 obtain 0.11 g of a light yellow oil, translated by treatment with excess HCl in the HCl-salt. By recrystallization from a mixture of ethyl acetate-hexane get the pure title compound in the form of snow-white matter so pl. 131 132oC.

1H-NMR (CDCl3, TMC): 7,28 of 6.78 (m, 3H), 6,18 of 5.92 (K, 2H), 6,6 5,24 (m, 3H), 405 (t, 1H), 3,84 (s, 3H), 3,83 of 1.55 (m, 10H), 0,91 0,8 (t, 3H).

IR (paste): lambda max 1630, 1600 and 1580 cm-1.

Example 45. ()-8-Trifluoromethyl-2-N-n-propylaminoethyl (H-9, scheme H)

Diastereomer 8-trifluoromethyl-2-N-[(R)--methylbenzyl] -2-N-n-propylaminoethyl received in connection with a lower value of Rfrehabilitation Mininova h in a Parr apparatus under a pressure of 50 psi (3.5 kg/cm2). Then the suspension is filtered through diatomaceous earth and the solvent is removed in vacuum. The residue is partitioned between ether and 10% aq. sodium carbonate. The ether layer is washed with water and brine. After drying over anhydrous magnesium sulfate and removal of solvent in vacuo obtain 5.6 g of a transparent liquid. So pl. HCl-salt (methanol-ether) 282oC (compound 45-And-enantiomer).

Example 46. (-)-8-Trifluoromethyl-2-N-n-propylaminoethyl (H-9, scheme H).

Diastereomer 8-trifluoromethyl-2-N-[(R)-a-methylbenzyl] -2-N-n-propylaminoethyl received in connection with a higher value of Rfduring the restoration aminating (see above), is subjected to hydrogenolysis according to the aforementioned method. So pl. HCl-salt (methanol-ether) 282oC (compound 47-B-enantiomer).

Example 47. (+)-8-Trifluoromethyl-2-N, N-di-n-propylaminoethyl (H-10, scheme H).

A mixture of (+)-8-Trifluoromethyl-2-N-n-propylaminoethyl (2 g), sodium carbonate (2.5 g), n-bromopropane (2.1 ml) and acetonitrile (18 ml) is boiled for 16 hours Then the solution is cooled and partitioned between ether and aq. sodium carbonate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent is removed in vacuum. Obtained> + 30,74(from 3.1 methanol) (1-isomer, compound 47).

Example 48. (-)-8-Trifluoromethyl-2-N, N-di-n-propylaminoethyl (H-10, scheme H).

According to the aforementioned method of (-)-8-Trifluoromethyl-2-N-di-n-propylaminoethyl alkylate. Salt of fumaric acid is so square (methanol-ether) 167oC []2D5= - 31,4C (from 2.67, methanol) (alpha-isomer, compound 48).

Example 49.

8-Bromo-2-N,N-di-n-propylaminoethyl (I-2, scheme I).

To a cooled to 0oC a mixture of 8-bromo-2-tetralone (25 g), methanol (110 ml), tetrahydrofuran (110 ml) and di-n-Propylamine (124 ml) was added glacial acetic acid (96 ml). After 10 min add cyanoborohydride sodium (15.5 g) and the mixture is stirred 18 h at room temperature. The solvent is removed in vacuo, to the residue is added ether and the solution extracted with aq. sodium carbonate. The ether layer is acidified with 2 N. HCl, the aqueous solution is extracted with ether, from which was derived the original compound (compound 49). The aqueous layer was alkalinized 15-Noah sodium hydroxide and extracted with ether. The ether layer is extracted with brine, dried over anhydrous sodium sulfate and after removal of the solvent in vacuo obtain 11 g of a yellow liquid (compound 49 is to -50oC to a solution of 8-bromo-2-N,N-di-n-propylaminoethyl (7.6 g) in tetrahydrofuran (50 ml) was added tributyltin (1.7 M in pentane, 32 ml) followed by addition over 15 minutes of dimethylformamide (9.5 ml). The solution is heated to room temperature and after addition of ether, washed with water and brine, dried over anhydrous sodium sulfate and removal of solvent in vacuo obtain 1.6 g of a yellow liquid.

Example 51. 8-(5-Oxazolyl-2-N,N-di-n-propylaminoethyl (I-4, scheme I).

A mixture of 8-formyl-2-N, N-di-n-propylaminoethyl (2 g), toiletrieschoice (1.5 g), methanol (15 ml) and potassium carbonate (2 g) is boiled to 2.75 hours, the Methanol is removed in vacuo, to the residue is added ether, the solution washed with water and brine, dried over anhydrous sodium sulfate and the solvent is removed in vacuum. Carry out chromatography on a column for pressure chromatography (2 x 30 cm) with silica gel and elution 25 ethyl acetate in hexane. So pl. HCl-salt (ether-acetonitrile 2,3 1) 160oC (compound 51a).

Example 52. 8-Aminosulfonyl-2-N-n-propylaminoethyl.

To a solution of 8-aminosulfonyl-2-tetralone (1.13 g, 5 mmol) in a mixture of tetrahydrofuran (10 ml) and methanol (25 ml) is added acetic acid (3 g, 50 mmol) and then n-Propylamine (1.5 to the g 10 mmol). The mixture is stirred 18 h at room temperature, the solvent is removed in vacuo and the residue partitioned between a mixture of diethyl ether-tetrahydrofuran (2 1) and diluted with ammonium hydroxide (pH 9 to 10). The ether solution was again washed with diluted ammonium hydroxide and the aqueous washing solutions are again shaken out three times with a mixture of diethyl ether-tetrahydrofuran (2 1).

The combined organic phase is dried (MgSO4) and after removal of the solvent in vacuo get amber oil (1,38 g), the oil is dissolved in a small amount of tetrahydrofuran and the solution is added an excess of HCl in ether. Then add the ether, the precipitate is centrifuged, washed with diethyl ether and after crystallization from methanol-diethyl ether to obtain 1.29 g of amine in the form of snow-white matter so pl. 257,5 258oC (HCl-salt, compound 52).

Example 53. 8-aminosulfonyl-2-(N-allylamino)tetralin.

The compound is synthesized analogously to obtain n-Propylenediamine 8-aminosulfonyl-2-tetralone (1.13 g, 5 mmol), allylamine (1.45 g, 25 mmol), acetic acid (3 g, 50 mmol), laborgerate sodium (0,63 g, 10 mmol), tetrahydrofuran (10 ml) and methanol (25 ml). Received 0,72 g of the hydrochloride allylamine">

Example 54. 8-Aminosulfonyl-2-(N, N-dipropylamino)tetralin (J-7, diagram J).

A mixture of 8-aminosulfonyl-2-tetralone (1.13 g, 5 mmol), dipropylamine (2.6 g, 25 mmol) and monohydrate p-toluenesulfonic acid (0.1 g, of 0.53 mmol) in benzene (30 ml), boiled for 19 h at the nozzle Dean-stark. Then add ethanol (30 ml) and platinum oxide (0.3 g) and the mixture hydronaut in the Parr apparatus under a pressure of 50 psi (3.5 kg/cm2within 5 hours the Mixture is filtered, the catalyst washed thoroughly with ethanol and the combined filtrate evaporated in vacuum. The residue is dissolved in a mixture of diethyl epitetracycline (2 1) and twice washed with diluted ammonium hydroxide (pH 9 to 10). Aqueous washing solutions are again washed with a mixture of diethyl ether-tetrahydrofuran (2 1), the extracts washed with brine and dried (MgSO4). Removal of solvent in vacuo get a brown oil (1,58 g). The compound obtained (1.3 g) is mixed with p-toluensulfonate (0.8 g) and crystallization of a mixture of methanol-diehtilovogo ether get dipropylenetriamine in the form of a yellow substance so pl. 192 and 194, 225 - 226oC (compound 54).

Example 55. 8-Aminosulfonyl-2[N-(3-phenylpropyl)amino]tetralin.

The compound was synthesized in a manner analogous to visarimetall), 3-phenyl-1-Propylamine (0.75 g, 5.3 mmol), p-toluenesulfonic acid (0.1 g, of 0.53 mmol) and platinum oxide (0.3 g) in benzene (20 ml) and ethanol (35 Il) obtaining 1,71 g of the solid product recrystallized from acetonitrile and transferred into the hydrochloride by the above method (so pl. 105 130oC) (compound 55).

Example 56. 8 Thiocarboxamide-2-(N,N-di-n-propylamino)tetralin.

To a cooled to -78oC a solution of 8-bromo-2-N,N-di-n-propylaminoethyl (620 mg) in THF added tert-utility (2 EQ.) and the solution is stirred for 5 minutes Then add trimethylsilylmethylamine (300 mg) and the solution allowed to warm to 0oC. After addition of water and ether, the reaction mixture is extracted. The organic layer was washed with brine, dried on anhydrous sodium sulfate and after removal of the solvent in vacuo get the title compound.

In table. 3 36 the data on the binding of 5-oxitriptan (5-HTIA).

1. Derivatives of 1,2,3,4-tetrahydro-2-naphtylamine General formula I

< / BR>
where R is hydrogen or co3;

R1hydrogen, HE, (C1WITH4)alkyl, -CONR7R8, het, where het the remainder of the five-membered heterocycle containing nitrogen, carbon, and in some cases color the5alkenyl,3WITH8-quinil, (CH2)m- (C3WITH8)cycloalkyl, -(CH2)m-aryl, trimethylsilylmethyl, -(CH2)m-CO2R6or C(O)CH3, R3has values of R2or (CH2)m-indole, substituted C1WITH4- alkoxyl, (CH2)m-6-phenyl-4H-5-triazolo(4,3-a) (1,4)benzodiazepine-1,6-phenyl substituted in the aromatic ring by halogen, [(2,3-dihydro-1,1-dioxo-3-oxopentanenitrile)-(CH2) n] -1,3-benzodioxolyl(CH2)n, R2and R3together with the nitrogen atom denote a group

R4hydrogen, C1WITH8-alkyl, C2- C8alkenyl, (CH2)m(C3C8-cycloalkyl, (CH2)mCO2R6the methylene;

R5hydrogen or C2WITH8alkenyl;

R6, R7and R8independently hydrogen, C1- C4-alkyl, C1WITH4-alkaryl;

X (CR6R6)n-, (CR6R6)n-O-(CR6R6)q-, (CR6R6)n-S-(CR6R6)q-; m is 0 to 4;

n 4 6;

p 0 1;

q 1 3;

and their pharmaceutical acceptable salts, provided that when R1hydroxyl or methoxy, R4and both R with the nitrogen atom, may not be the piperidine; when R1--CONH2, R2and R3both can not be cut, when R1, R4and R5hydrogen, one of R2or R3is hydrogen and the other may not be ethylene.

2. Connection on p. 1, characterized in that they are selected from the group including 8-(oxazol-5-yl)-1,2,3,4-tetrahydro-2-N, N-di-n-propylaminoethyl or its hydrochloride, 8-(3-bromination 5-yl)-1,2,3,4-tetrahydro-N, N-di-n-propylaminoethyl or its hydrochloride.

3. Connection on p. 1, wherein R1- CONR7R8.

4. Connection on p. 3, characterized in that the radical-CONR7R8presents N-alkylaminocarbonyl.

5. Connection on p. 3, wherein selected from the group comprising 1,2,3,4-tetrahydro-2-N, N-di-n-propylaminoethyl-8-yl-N-benzylcarbamoyl or its salt with maleic acid, 1,2,3,4-tetrahydro-2, N,N-dicyclopentadienyl-8-yl-N-methylcarbamate, 1,2,3,4 - tetrahydro-2-N-cyclopropylmethanol-8-yl-N-methylcarbamate.

6. Connection on p. 4, characterized in that it presents 1,2,3,4-tetrahydro-2-N,N-dipropylamino-8-yl-N-methylcarbamate.

7. Connection on p. 1, characterized in, h is trihydro-2-N, N - dicyclopentadienyl-8-yl))(2-pyrrolyl)ketone.

9. Connection on p. 1, wherein R2and R3together with the nitrogen atom to which they are attached, form a loop

10. Connection on p. 9, wherein selected from the group consisting of CIS-2,6-dimethyl-4-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl) morpholine, TRANS-2,6-dimethyl-4-(1,2,3,4 - tetrahydro-8-methoxy-2-naphthalenyl)morpholine, 4-(1,2,3,4 - tetrahydro-8-methoxy-2-naphthalenyl)thiomorpholine or its hydrochloride, 7-(hexahydro-1-(2H)-azocine)-1-methoxy-5,6,7,8 - tetrahydronaphthalen or its hydrochloride, 7-(hexahydro-1(2H)-azocine)-5,6,7,8-tetrahydro-1-naphthalenol or its hydrochloride, 2-(1-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalen or its hydrochloride.

11. Connection on p. 1, wherein R4selected from the group including C1C8-alkyl, C3WITH8alkenyl, -(CH2)mWITH3WITH8-cycloalkyl,- (CH2)m< / BR>
CO2R6where R6and m have values under item 1.

12. Connection on p. 11, wherein selected from the group comprising TRANS-1,2,3,4-tetrahydro-8-methoxy-1-(2-propylene)- N-propyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N, N - dipropyl-2-norid; CIS-1,2,3,4-tetrahydro-8-methoxy-N, 1-dipropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4 - tetrahydro-8-hydroxy-N,1-dipropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-hydroxy-N,N,1-tripropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N,N-1 - tripropyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4 - tetrahydro-8-methoxy-N,1-di-2-propenyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-N, 1-di-2-propenyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4 - tetrahydro-8-methoxy-1-cyclopropylmethyl-N-propyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-1-cyclopropylmethyl-N-propyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N,1-bis-cyclopropylmethyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N-cyclopropylmethyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-N,1-biscyclopentadienyl-2-naphtylamine, or its hydrochloride,

TRANS-1,2,3,4-tetrahydro-8-methoxy-1-(2-propenyl)-N-cyclopropylmethyl - 2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-1-(2-propenyl)-N - propyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4- -tetrahydro-1- (2-propenyl)-N-propyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-5-methoxy-1-(2-pramin or its hydrochloride; CIS-1,2,3,4-tetrahydro-1-hydroxymethyl-8-methoxy-N-propyl-2-naphtylamine or its hydrochloride; CIS-1-(cyclopropylmethyl)-1,2,3,4-tetrahydro-8 - methoxy-2-propenyl-2-naphtylamine or its hydrochloride; TRANS-1-(cyclopropylmethyl)-1,2,3,4-tetrahydro-8-methoxy-N - 2-propenyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4 - tetrahydro-8-methoxy-1-hydroxymethyl-N-2-propenyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-1-hydroxymethyl-N-2-propenyl-2-naphtylamine or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-hydroxy-N, 1-di(2-propenyl)-2-naphtylamine or its hydrochloride.

13. Connection on p. 1, wherein R1a methoxy group, R5-C2WITH8alkenyl, and R2and R3take the value under item 1.

14. Connection on p. 13, wherein selected from the group consisting of CIS-1,2,3,4-tetrahydro-8-methoxy-N,3-dipropyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4-tetrahydro-8-methoxy-N,3-dipropyl-2-naphtylamine, or its hydrochloride, CIS-1,2,3,4-tetrahydro-8-methoxy-3-propenyl-N-n-propyl-2-naphtylamine or its hydrochloride; TRANS-1,2,3,4 - tetrahydro-8-methoxy-3-propenyl-N-n-propyl-2-naphtylamine or its hydrochloride.

15. Connection on p. 1, wherein R2and R3the same or different animal value under item 1, provided that when one of R2or R3hydrogen, then the other cannot be 1-propanolol.

16. Connection on p. 15, wherein selected from the group comprising 1,2,3,4 - tetrahydro-8-methoxy-N,N-di-2-PROPYNYL-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N - 2-PROPYNYL-2-naphtylamine; 1,2,3,4-tetrahydro-8-methoxy-N-2 - propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4 - tetrahydro-8-methoxy-N, N-di-2-propenyl-2-naphtylamine or its hydrochloride; N-ethyl-1,2,3,4-tetrahydro-8-methoxy-N-(2 - methyl-2-propenyl) -2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-hydroxy-N-2-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-(2-methyl-2-propenyl)-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-N-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-methoxy-N-methyl-N - 2-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4 - tetrahydro-8-methoxy-N-methyl-N-(2-methyl-2-propenyl)-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-N-2-PROPYNYL-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-hydroxy-N, N-di-2-propenyl-2 - naphtylamine or its hydrochloride; 1,2,3,4 - tetrahydro-8-methoxy-N-methyl-N-2-PROPYNYL-2-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-N, N-di-2-propenyl-2-naphtylamine or its hydrochloride; 1,2,3,4-tetrahydro-8-marks the min or its hydrochloride; CIS-1,2,3,4-tetrahydro-8-methoxy-N-methyl-1-hydroxymethyl-N - n-propyl-2-naphtylamine or its hydrochloride; N-(cyclopropylmethyl)- 1,2,3,4-tetrahydro-8-methoxy-2-naphtylamine or its hydrochloride; N-(cyclopropylmethyl)-1,2,3,4-tetrahydro-2-naphtylamine or its hydrochloride; N-(cyclopropylmethyl)-1,2,3,4 - tetrahydro-8-hydroxy-2-naphtylamine or its hydrochloride and 1,2,3,4 - tetrahydro-N-methyl-N-n-propyl-2-naphtylamine or its hydrochloride.

17. Connection on p. 16, wherein selected from the group comprising 1,2,3,4-tetrahydro-N-2-propenyl-2-naphtylamine or its hydrochloride.

18. Connection on p. 16, wherein selected from the group comprising 1,2,3,4-tetrahydro-8-methoxy-N - methyl-N-2-propenyl-2-naphtylamine or its hydrochloride.

19. Connection on p. 16, characterized in that it presents 1,2,3,4-tetrahydro-8-methoxy-N-methyl-N-2-PROPYNYL-2-naphthylamine.

20. Connection on p. 1, characterized in that it is a compound of the General formula I

< / BR>
where R1, R2, R3, R4have the values listed in paragraph 1.

21. Connection on p. 20, wherein selected from the group comprising 1,2,3,4-tetrahydro-1-methenyl-8-methoxy-N- (2-propenyl)-N-n-propyl-2-naphtylamine, or its hydrochloride, 1,2,3,4 - tetrahed the different topics which R is hydrogen, R1selected from the group including CF3, -SO2NH2and 5-oxazolyl, and R2and R3may be the same or different and are selected from the group including hydrogen and C1WITH8-alkyl.

23. Connection on p. 1, wherein selected from the group comprising (+)-8-trifluoromethyl-2-N-n-propylaminoethyl, (-)-8-trifluoromethyl-2-N - n-propylaminoethyl, (+)-8-trifluoromethyl-2-N, N - di-n-propylaminoethyl, (-)-8-trifluoromethyl-2-N, N - di-n-propylaminoethyl, 8-bromo-2-N,N - di-n-propylaminoethyl, 8-formyl-2-N, N-di-n-propylaminoethyl, 8-(5-oxazolyl)-2-N, N-di-n-propylaminoethyl, 8-aminosulfonyl-2-N-n-propylaminoethyl, 8-aminosulfonyl-2-(N-allylamino)tetralin, 8-aminosulfonyl-2-(N, N-dipropylamino)tetralin, 8-aminosulfonyl-2-[N-(3 - phenylpropyl)amino]tetralin.

 

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