Derivatives of 1,2,3,4-tetrahydronaphthalene, methods for their preparation, pharmaceutical composition and method of treatment

 

(57) Abstract:

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, F2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl. The compounds of formula (I) possess antagonistic activity against receptor 5-HT1Band can find application in medicine. 10 C. and 22 C.p. f-crystals, 2 tab., 1 Il.

The invention otnositsa, (S)-enantiomers or racemates, in the form of their free base or pharmaceutically acceptable salts, method of production thereof, to pharmaceutical compositions containing the named therapeutically active compounds and to the use of the named active compounds in therapy.

The aim of the invention is to provide compounds for therapeutic purposes, in particular compounds with selective effects on the subgroup of 5-hydroxy-tryptamine receptors, referred to as h5-HT1receptor (previously known as 5-HT1Dreceptor), in mammals, including humans.

Another purpose of the invention is to provide compounds with therapeutic effect after oral administration.

Art

Different classes piperazineethanesulfonic derived benzanilide, such as antagonists of 5-HT1Dare disclosed, inter alia in European patent 533266, EP 533267, EP 533268, GB 227930 and WO 95/11243.

WO 94/13659 reveals a very wide class of condensed benzodiazipine with para-substituted piperidinyl or piperazinilnom radical in the aromatic ring, and argues that these class of compounds binds to 5-HT1A-receptor.

1)

EP 402923 discloses 2-aminoaniline or alkylaromatics derivatives of 1,2,3,4-getagedonline with additional nitrogen Deputy 5 position in tetralinea the ring, and these compounds act as antagonists of dopamine.

Justification of the invention

It turned out that various diseases of the Central nervous system such as depression, anxiety and other include violation of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also known as serotonin. I believe that drugs most often used in the treatment of depression work by enhancing neurotransmission each or both of these physiological agonists. It turned out that increasing 5-HT neurotransmission primarily affects depressive mood and anxiety, while increasing noradrenergic neurotransmission affects the symptoms of mental retardation (amentia) occurring in patients in a state of depression. The invention relates to compounds that act on 5-HT neurotransmission.

Is chtoto the increased activity of 5-HT is associated with anxiety, while the reduction in the release of 5-HT is associated with depression. In addition, serotonin is involved in such painful conditions as malnutrition, gastrointestinal diseases, cardiovascular regulation and disorders of sexual behavior.

5-HT receptors

Different effects of 5-HT may be associated with the fact that serotonergic neurons stimulate the secretion of several hormones, such as cortisol, prolactin, -endorphin, vasopressin and others. It turns out that the secretion of each of these hormones is regulated specifically in several different 5-HT (serotonin) receptor subtypes. Thanks to the techniques of molecular biology to date, these receptors are classified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6and 5-HT7moreover , the receptor 5-HT1in turn subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1Eand 5-HT1Fsubtypes. Each subtype receptor are involved in various serotonin function and has different properties.

Regulation of 5-HT transmission

The release of 5-HT in the nervous system is regulated by feedback principle two different subtypes of 5-HT receptory during stimulation of 5-HT reduces the momentum distribution in 5-HT neurons, thus reducing the release of 5-HT at nerve endings. Another subtype of inhibitory 5-HT receptor 5-HT nerve endings are h5-HP1Breceptors in rodents r5-HT1Breceptors), which regulate synaptic concentration of 5-HT, by controlling the number of released 5-HT. The antagonist of this terminal autoreceptor, thus, increases the number of 5-HT released from the nerve impulse, which as shown in experiments in vitro and in vivo.

The use of antagonist terminal h5-HT1Breceptor will correspondingly increase the synaptic concentration of 5-HT and to increase the transmission in the 5-HT system. Thus the antidepressant effect, making it suitable for the treatment of depression.

Also there is another localization of receptor subtype h5-HT1BIt turned out that most of these postsynaptic receptors located in the nerve endings of the other systems of neurons (the so-called heteroreceptors). Since h5-HT1Bthe receptor mediates inhibitory responses, the antagonist of this receptor subtype may also increase the release of other neurotransmitters than 5 Diverse pharmacological tests can be divided into full agonists, partial agonists and antagonists.

Disclosure of the invention

The aim of the present invention is to provide compounds having a selective effect on the h5-HT1Breceptors, preferably having antagonistic properties, as well as having good bioavailability. Studied the effects on other receptors, selected from 5-HT1A, 5-HT2AD1D2AD3,1and2the receptor.

Accordingly, the present invention provides compounds of formula I,

< / BR>
where X represents N or CH;

Y represents NR2CH2CH2-NR2, NR2-CO, CO-NR2or NR2SO2,

where R2represents H, C1-C6-alkyl;

R1represents H, C1-C6-alkyl, C3-C6-cycloalkyl;

R3represents a C1-C6-alkyl, C3-C6-cycloalkyl or (CH2)n-aryl,

where aryl represents phenyl or a heterocyclic ring containing one or two heteroatoms selected from N or O and S and which may be single - or disubstituted R4and/or R5;

where R4represents H, C1, F3, SO3CH3, SO3CF3, SO2NR6R7, phenyl, phenyl-C1-C6-alkyl, phenoxy, C1-C6-alkylphenyl, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2where the substituent(s) selected(s) from C1-C6-alkyl, C3-C6-cycloalkyl and phenyl-C1-C6-alkyl, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N or O and S, where the substituent(s) selected(s) from C1-C6-alkyl, C3-C6-cycloalkyl and phenyl-C1-C6-alkyl, or COR8;

where R6represents a C1-C6-alkyl or C3-C6-cycloalkyl;

R7represents H, C1-C6-alkyl or C3-C6-cycloalkyl; and

R8represents a C1-C6-alkyl, C3-C6-cycloalkyl, CF3, NR6R7, phenyl, heteroaromatic ring containing one or more heteroatoms selected from N, O and S, or a heterocyclic ring containing one or more heteroatoms selected from N, O, S, SO and SO2;

where R5;

n is 0-4;

R9represents a C1-C6-alkyl, C3-C6-cycloalkyl, F3, OCHF3, OCH2F, halogen, CN, CF3HE1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O and S, where the substituent(s) is(are) a C1-C6-alkyl; or COR8; where R6, R7and R8such as defined above,

in the form of (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or MES, which are highly selective effect on the h5-HT1Breceptors, and also have sufficient bioavailability in oral administration.

In the context of the present invention C1-C6the alkyl may be straight or branched chain. C1-C6the alkyl may be a methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, n-pentyl, out-of pentyl, tert-pentyl, neo-pentyl, n-Huck is Oh or branched chain. C1-C6the alkyl may be a methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, ISO-pentyloxy, tert-pentyloxy, neo-pentyloxy, n-hexyloxy or out-hexyloxy.

In the context of the present invention WITH3-C6-cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In the context of the present invention, the halogen may be fluorine, chlorine, bromine or iodine.

In the context of the present invention heteroaromatic ring; contains one or two heteroatoms selected from N, O and S, preferably represents a 5-or 6-membered heteroaromatic ring, and can be a furyl, imidazole, isoxazol, isothiazol, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. Heteroaromatic ring may be substituted, or unsubstituted.

In the context of the present invention heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2does not necessarily contain a carbonyl functional group, and preferably represents a 5 - to 6 - or 7-the sludge, piperidyl, piperidinyl, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydropyranyl, thiomorpholine, preferably piperidino, 1-piperazinil, morpholine, thio-morpholine and 4-piperidin-1-yl.

The preferred embodiment of the invention relates to compounds of formula I, where Y is NHCO or CONH, i.e. amides. Of these compounds, preferred are such compounds in which R9represents a C1-C6-alkyl, C1-C6-alkoxy, OCHF2or OCH2F, and R3represents unsubstituted phenyl or mono - or di-substituted phenyl, in particular ortho-, meta - or para-substituted phenyl, and in particular those in which R4represents phenyl, phenyl-C1-C6-alkyl, cyclohexyl, piperidine, 1-piperazine derivatives, morpholine, CF3, 4-piperidin-1-yl, n-butoxy or COR8where R8represents phenyl, cyclohexyl, 4-piperidin-1-yl, 1-piperazinil, morpholino, CF3, piperidino or NR6R7.

Examples of combinations of the substituents are the following:

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2is the and3H7;

X represents CH, Y represents CONR2R represents H, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3C2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents piperidino, R5represents H, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3C2H5or3H7, R;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents morpholino, R5represents H, R9represents CH3C2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5ecstasy a phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents piperidino, R5represents H, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents piperidino, R5represents H, R8is a co3;

X represents N, Y represents CONR2, R1represents N, CH3C2H5or3H7, R2provided is a cyclohexyl, R9represents CH3C2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3C2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH2C2H5or3H7, R2represents H, R3represents CH2-phenyl, R9represents CH2WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents piperidino, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents Oh, H, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3C2H5or3H7, R2represents H, R3represents phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3C2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3C2H5or3H7, R2represents H, R2represents (CH2)2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3C2H5or3N3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents piperidino, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3C2H5or3H7, R2represents H, R3represents phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl>represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents piperidino, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R9represents (CH2)2-phenyl, R4represents Moholi the hat is CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4is a FeNi is B>5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents piperidino, R5represents H, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3the submitted the hat is the co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4is a COR8, R8represents morpholino, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3not only is a H, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4is a COR8, R8represents morpholino, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents with dstanley a N, R3represents (CH2)2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents piperidino, R5represents H, R9is a co3;

X represents CH, a represents a CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R9is a co3;

X represents N, Y represents CONR2, R1predsedatelem a phenyl, R4is a COR8, R8represents cyclohexyl, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R9is a co3;

X represents CH, a represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4is a COR8, R8represents NR6R7, R6R7CH3WITH2H5or3H7, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2present the UB>2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3is a dryer which SUB> WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5go3H7, R2represents H, R3represents (CH2)2-phenyl, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4is a COR8, R8represents NR6R7, R6R7CH3WITH2H5or3H7, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3With3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents a piperidine, R5represents H, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4is particularly the/SUB>H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9is a co3;

X represents CH, Y represents CONR2, R1represents N, CH3)2-phenyl, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4is piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)-phenyl, R" is CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents , WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4is piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITHrepresents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents morpholino, R5represents H, R9represents CH3<1 represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents phenyl, phenylmethyl, phenylethyl, R5represents H, R9is a co3;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4is a COR8, R8represents morpholino, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R39represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents CH, Y represents establet a N, R3represents phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R4is a COR8, R8represents morpholino, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4predstavljaet2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents phenyl, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents morpholino, R5represents H, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents CONR2, R1represents N, CH3WITH2HIl, R4represents piperidino, R5represents H, R9is a co3;

X represents N, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents morpholino, R5represents H, R9is a co3;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R4represents phenyl, phenylmethyl, phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

X represents N, Y represents CONR2, R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents piperidino, R5represents H, R9represents CH3WITH2H5or3SUB>3WITH2H5or3H7, R2represents H, R3represents (CH2)2-phenyl, R9represents CH3WITH2H5or3H7;

X represents CH, Y represents NR2CO., R1represents N, CH3WITH2H5or3H7, R2represents H, R3represents CH2-phenyl, R4represents phenyl, phenylmethyl or phenylethyl, R5represents H, R9represents CH3WITH2H5or3H7;

Preferred compounds

(R)-N-[5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl;

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-cryptomelane;

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-bromo-8-(piperazine-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzene;

(R)-N-[5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-methoxymethyl-8-(4-methylpiperazin-1 and the Teal]-4-morpholinomethyl;

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinosydnonimine;

N-(4-morpholinyl)-8-(4-methylpiperazine)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide;

N-(morpholinoethyl)-8-(4-methylpiperazin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide;

(R)-N-[5-ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -(4-morpholinoethyl)benzamide;

(R)-N-[5-deformedarse-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl and

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl.

Compounds of the present invention exist in the form of racemates or (R)- or (S)-enantiomers, in the form of free base or pharmaceutically acceptable salt or MES. Connections in the form of (R)-enantiomers are preferred.

For the formation of a non-toxic pharmaceutically acceptable salts accession acid compounds of the present invention apply both organic and inorganic acids. Examples of acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, bromistogo Sultanova, succinic, propionic, glycolic, malic, gluconic, peruvemba, phenylacetic, 4-aminobenzoic, Anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,5-dihydroxybenzene, 3,5-dihydroxybenzene, 3-hydroxy-2-naphthoic, nicotine, methansulfonate, econsultancy, hydroxyethanesulfonic, benzolsulfonat, para-toluensulfonate, sulfanilic, naphthalenesulfonate, ascorbic, cyclohexylsulfamate, fumaric, maleic and benzoic acid. These salts can be easily obtained by methods known from the prior art.

The preferred solvate compounds are hydrates.

Pharmaceutical compositions

In a second aspect the present invention provides a pharmaceutical composition (preparative form), containing as active ingredient a therapeutically-effective amount of compounds of formula I in the form of an enantiomer or racemate in the form of their free base or pharmaceutically-acceptable salt or MES, optionally in combination with diluents, excipients or inert carriers.

In accordance with the present invention compounds

the present invention generally applied Pero ingredient in the form or free base, or pharmaceutically acceptable non-toxic salt accession acids, such as hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulpham, citrate, tartrate, oxalate, and the like in a pharmaceutically acceptable dosage form. Dosage form may be a solid, semisolid or liquid preparation. Usually the active substance is from 0.1 to 99% by weight of the preparation, more specifically from 0.5 to 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.

To obtain a finished pharmaceutical formulations of compounds of the present invention in the form of a unit dosage forms for oral application, the selected compound may be mixed with solid excipients, for example lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, binders such as gelatin or polyvinylpyrrolidone, and lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If you need tabla is sugar, which may contain, for example, gum Arabic, gelatin, talc, titanium dioxide, and the like. On the other hand, the tablets can also be coated with polymers known in the art in this technical field, dissolved in a volatile organic solvent or mixture of organic solvents. Dyes can be added to the coating for ease of differences between tablets containing different active substances or different number of active connections.

To obtain soft gelatin capsules, the active substance can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substance, and use or excipients described above for tablets, for example lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives, or gelatin. Hard gelatin capsules can be filled with liquid go semi-solid drugs.

Dosage unit form is a standard dose for rectal application can be a solution or suspension of, or can be prepared in fo the selected capsules, contains the active substance in a mixture with vegetable oil or paraffin oil. Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, for example solutions containing from about 0.1% to about 20% by weight of the active substances described here, the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparation may contain colouring agents, flavouring agents, saccharine or carboxymethylcellulose as a thickening agents or excipients known to specialists in this field.

Solutions for parenteral administration by injection can be obtained in the form of an aqueous solution of water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.1% to about 10% by weight. These solutions may also contain stabilizing agents or buferiruemoi agents and can be conveniently represented in the form of ampoules with a specific standard dose.

A suitable daily dose of a compound according to the invention in therapeutic treatment of humans is about 0.01-100 mg/kg BW after oral administration and 0.001-100 mg/kg body weight at parenteral administration.

1A
antagonist, such as compounds disclosed in WO 96/33710, preferably (R)-5-carbarnoyl-3-(N,N-dicycloverine)-8-fluoro-3,4-dihydro-2H-1-benzopyran.

Medical and pharmaceutical use

Another aspect of the present invention is the use of compounds of formula I in therapy as antagonists h5-HT1Bpartial agonists or full agonists, preferably as antagonists, and the use in the treatment of diseases mediated by 5-hydroxytryptamine. Examples of such diseases are diseases of the CNS, such as mood disorders (depression, large depressive episodes, dysthymia, seasonal affective disorder, depressive phase of bipolar disorder), anxiety (obsessive-compulsiveness anxiety, post-traumatic stress), personality disorders (disorders of impulse control, trichotillomania), obesity, anorexia, bulimia, premenstrual syndrome, sexual disorders, alcoholism, abuse of tobacco, autism, attention-deficit, hyperactive state, migraine, memory disorders (age-related memory impairment, presenilny and senile dementia), pathological aggression, schizophrenia, endocrine disorders (e.g., hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease, impaired thermoregulation, pain, hypertension. Other examples of diseases mediated hydroxytryptamine are incontinence, vasospasm and control of tumor growth (for example, carcinoma of the lung).

Ways to get

The present invention also relates to methods of preparing compounds of formula I. From the following description of this process it becomes clear that, where necessary, suitable protective groups are added (and removed) to various reagents and intermediate products, and ways that are understandable to experts in the field of organic synthesis. Conventional methods for use of such protective groups, as well as the ptx2">

Methods of obtaining intermediate compounds

1. In the case where Y represents NR2CO and X represents N

(i) Benzylidene the compounds of formula II, or in the form of a racemate or as an enantiomer,

< / BR>
Obtaining the compounds of formula III can be carried out by reaction with a suitable Basilisk agent, such as benzylalkonium, such as benzylbromide or benzylchloride, or active alcohol, such as benzylmethylamine or benzalconium. The reaction may be carried out using the salt or the base of the compound II in a suitable solvent, for example N,N-dimethylformamide, acetone or acetonitrile, with an appropriate base, for example NaOH, Panso3TO2CO3or trialkylamines, such as triethylamine, at a temperature of from +20 to +150oC. the Presence of a suitable catalyst, such as potassium iodide or sodium iodide may increase the reaction rate. The nitrogen in compound II may also be protected by reductive alkylation with arilaldegidov in the presence of a reducing agent, such as cyanoborohydride sodium, sodium borohydride or catalytically with2and a suitable catalyst containing palladium, platinum, rhodium or Nickel in the as pair-toluensulfonate acid, can be used for catalysis education Imin/enamine, and bringing the pH to slightly acidic, the appropriate acid, such as acetic acid, can accelerate the reaction, which resulted in the receive connection III.

(ii) Demethylation of compounds of formula III

< / BR>
Obtaining the compounds of formula IV can be carried out by treating the compounds with acidic reagents, such as HBr, HI, NWG/CH3COOH, VVG3, ll3, pyridine-Hcl or basic nucleophilic reagent such as CH3WITH6H4S-or2H5S-in a suitable solvent. Suitable solvents can be methylene chloride or chloroform, and the reaction can be carried out at -78oC and +60oC.

(iii) the Conversion of compounds of formula IV to the compound of formula V

< / BR>
can be performed by reaction with a compound of formula VI

< / BR>
where X represents a removable group, for example, halogen, such as chlorine, bromine or iodine, or a group of alkane - or arenesulfonic, such as pair-toluensulfonate group, and Raand Rbrepresent hydrogen or a lower alkyl group, for example methyl. The process can be carried out with a salt of the compound of the formula is eacce can be carried out in an appropriate solvent, for example in an aprotic solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran, toluene, benzene, or petroleum ether, and the reaction may proceed at temperatures from +20oC to +150oC.

(iv) the Conversion of compounds of formula V to the compound of formula VII

< / BR>
can be carried out in a suitable solvent (for example, aprotic solvent such as N,N-dimethylformamide, dioxane, 1,1,3,3-tetramethylrhodamine, tetrahydrofuran or triamide hexamethylphosphoric acid with an appropriate base, such as2CO3, CON, tert-piperonyl NaH or potassium, at a temperature in the range from +20oC to +150oC.

The presence of co-solvent such as 1,3-dimethyl-3,4, 5,6-tetrahydro-2(1H)-pyrimidone or triamide hexamethylphosphoric acid in the corresponding concentration in the solvent can increase the speed of reaction.

(v) Hydrolysis of compounds of formula VII to the compound VIII can be carried out in acidic conditions using acids such as H2SO4, HCl or NVG in a suitable solvent, such as H2O, ethanol, methanol or mixtures thereof and the reaction may occur between +20oC to +100oWith, or under alkaline conditions, with IP is, or mixtures thereof, and the reaction may occur between +20oC to +100oC.

(vi) the Conversion of compounds of formula VIII to the compound of formula IX

< / BR>
can be done by

a) reaction with the compound of the formula X

< / BR>
where R1represents a C1-C6alkyl or C3-C6-cycloalkyl. The process can be carried out in a suitable solvent, for example an aprotic/anhydrous solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of coupling reagent such as N,N-carbonyldiimidazole, and the reaction may occur between +20oC to +130oC. the reaction should restore imide using appropriate reducing agent, such as LiAlH4in a suitable solvent, such as diethyl ether or tetrahydrofuran at a temperature between +20oC and boiling under reflux, or

b) reaction of a compound of formula XI

< / BR>
where X represents a removable group, for example halogen, such as chlorine or bromine, or a group of alkali - or arenesulfonic, such as pair-toluensulfonate group, and R1represents H, C1-C6-alkyl or C3-C6-cycloalkyl. The process is ü water and acetonitrile with a suitable base, such as2CO3, Panso3or KOH, and the reaction may occur between +20oC to +150oC.

(vii) a Compound of formula IX can also be obtained by benzylalkonium the compounds of formula LVIII where Rcis a halogen, such as chlorine, bromine or iodine, in the form of its racemate or enantiomer.

< / BR>
obtaining the compounds of formula LIX, by reaction with the corresponding Basilisk agent, such as benzylalkonium, such as benzylbromide or benzylchloride, or active alcohol, such as benzylmethyl or benzalconium. The reaction may be carried out using the salt or the base compound LVIII in an appropriate solvent, for example N,N-dimethylformamide, acetone or acetonitrile, with an appropriate base, for example NaOH, Panso3TO2CO3or trialkyl-amine, such as triethylamine, at a temperature in the range from +20oWith up to 150oC. the Presence of a suitable catalyst, such as potassium iodide or sodium iodide may increase the reaction rate.

(viii) the Conversion of compounds of formula LIX in the compound of formula IX, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, m is in a suitable solvent, for example in an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide, with an appropriate base, such as tert-piperonyl or sodium bis (trimethylsilyl)amide lithium, in the presence of a suitable palladium catalyst, such as PdX2, L2Pd(0) or L2PdX2where X represents halogen, such as chlorine or bromine, and L represents a suitable ligand, such as triphenylphosphine, tri-o-tolylphosphino, triphenylphosphine, triphenylarsine or dibenzylideneacetone, and with or without added ligand L', such as triphenylphosphine, tri-o-tolylphosphino, triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (or in the form of a racemate or enantiomer), or triphenylarsine, and the reaction may proceed at temperatures ranging from +20oC to +150oWith, resulting in obtaining the compounds of formula IX.

The transformation of LIX in the IX also occurs through the transformation of the XXII in aminocandin or aminoborane, using such agents as (N,N-diethylamino)tributylamine or Tris(dimethylamino)borane in a suitable solvent, for example in an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide, and then using conditions similar to the mules IX, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl,

< / BR>
to obtain the compounds of formula XII can be carried out in aromatic electrophilic substitution using a suitable halogenation agent such as VG2, Cl2, I2, Il2or SO2Cl2. The reaction may be carried out using the salt or the base of the compound IX in an appropriate solvent, for example acetic acid, HCl/ethanol or water, with or without a suitable base, such as alkali metal acetate such as sodium acetate, and the reaction may proceed at temperatures ranging from -20oWith up to room temperature.

The compound of formula XII can also be obtained by benzylidene the compounds of formula IX to obtain the compounds of formula XII by reaction with a suitable Basilisk agent, such as benzylalkonium, such as benzylbromide or benzylchloride, or active alcohol, such as benzylmethylamine or benzalconium in a suitable solvent, for example N,N-dimethylformamide, acetone or acetonitrile with a suitable base, for example NaOH, Panso3TO2CO3or trialkylamines, such as for example potassium iodide or sodium iodide, can increase the reaction rate.

< / BR>
(x) the Conversion of compounds of formula XII to a compound of formula XIII, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, and R9represents a C1-C6alkyl, may be carried out by exchange reactions of metal-halogen in an appropriate anhydrous solvent such as Tetra-hydrofuran or diethyl ether, using a suitable alkyl-lithium or metal, for example, utility, lithium or magnesium turnings, followed by treatment of the corresponding alkylhalogenide, such as methyliodide, ethylbromide or propyliodide, and the reaction may proceed at temperatures ranging from -78oWith up to room temperature, followed by removal of the benzyl group by hydrogenation in the presence of a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, for example acetic acid or ethanol and at a reaction temperature between +20oC to +120oWith or by treatment with other electrophiles, such as acetaldehyde or methylchloroform, and thereafter the corresponding final processing. The reaction may proceed when the reaction is of Avila used acetaldehyde, for the above reaction is followed by recovery to the benzyl alcohol and the removal of benzyl groups by hydrogenation with the participation of a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, for example acetic acid or ethanol, and the reaction may proceed at temperatures from +20oC to +120oC.

In the case where the electrophile is used methylchloroform, for the above reaction is followed by recovery to the methyl ester in a suitable solvent, such as diethyl ether or tetrahydrofuran, using an appropriate reducing agent, such as alumalite lithium, and the reaction may proceed at temperatures from +20oC to the boiling temperature under reflux, followed by removal of benzyl groups and recovery of benzyl alcohol by hydrogenation with the participation of a suitable catalyst containing palladium, rhodium, platinum or Nickel in a suitable solvent, such as acetic acid or ethanol, and the reaction may proceed at temperatures from +20oC to +120oC.

When R1represents hydrogen, before processing stage compound lithium AZ, zvetnoi specialists in this area, and then remote by known methods, resulting in the compound of formula XIII.

(xi) the Compound of formula XIII, where R1represents hydrogen, can be obtained

< / BR>
the transformation of compounds of formula LIX in the compound of formula LX, by reaction with a compound of formula LXI, where Rcrepresents a suitable protective group such as benzyl group

< / BR>
The process can be carried out in a suitable solvent, for example an aprotic solvent, such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide, with a suitable base, such as tert-piperonyl or sodium bis(trimethylsilyl)amide lithium, in the presence of a suitable palladium catalyst, such as PdX2, L2PD(O) or L2PdX2where X represents halogen, such as chlorine or bromine, and L represents a suitable ligand, such as triphenylphosphine, thio-o-tolylphosphino, triphenylphosphine, triphenylarsine or dibenzylideneacetone, and with or without added ligand L', such as triphenylphosphine, tri-o-tolylphosphino, triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (or its racemate or enantiomer) or triphenylarsine, and the reaction may Ave the

Turning LIX LX can also flow through the transformation LXI in aminocandin or aminoborane, using such agents as (N,N-diethylamino)tribution or Tris(dimethyl-amino)borane in a suitable solvent, for example an aprotic solvent, such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide, and then using the same conditions described in the above description, the obtained compound of formula LX.

(xii) Halogenoalkane the compounds of formula LX,

< / BR>
obtaining the compounds of formula LXII can be performed by aromatic electrophilic substitution using a suitable halogenation agent such as VG2, Cl2, I2, ICl or SO2CL. The reaction can be carried out using the salt or the base of the connection LX in an appropriate solvent, for example, acetic acid, HCl/ethanol or water, with or without a suitable base, such as alkali metal acetate such as sodium acetate, and the reaction may proceed at temperatures from -20oWith up to room temperature.

< / BR>
(xiii) the Conversion of compounds of formula LXII in the compound of formula XIII, where R1represents hydrogen, and R9predstavitveno solvent, such as tetrahydrofuran or diethyl ether, with suitable alkylate or metal, for example, utility, lithium or magnesium turnings, followed by treatment of the corresponding alkylhalogenide, such as methyliodide, ethylbromide or propyliodide, and the reaction can be carried out at reaction temperatures ranging from -78oWith up to room temperature, followed by removal of benzyl groups by hydrogenation in the presence of a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, such as acetic acid or ethanol, and the temperature of the reaction mixture from +20oWith up to 120oWith, or by treatment with other electrophiles, such as acetaldehyde or methylchloroform, and subsequent appropriate treatment. The reaction may be conducted at temperatures ranging from -78oWith up to room temperature.

When as electrophile acetaldehyde is used for the above reactions should restore benzyl alcohol and the removal of benzyl groups by hydrogenation using a suitable catalyst containing palladium, rhodium, platinum or Nickel, are eligible isC to +120oC.

When as the electrophile is used methylchloroform, for the above reactions should restore methyl ester in a suitable solvent, such as diethyl ether or tetrahydrofuran, using an appropriate reducing agent, such as alumalite lithium and the reaction may occur at temperatures from +20oWith up to boiling under reflux, followed by removal of benzyl groups and recovery of benzyl alcohol by hydrogenation using a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, such as acetic acid or ethanol, and the reaction may proceed at temperatures from +20oC to +120oC.

(xiv) the Conversion of compounds of formula XIII, where R1represents hydrogen, the compound of formula XIV

< / BR>
where Rcrepresents a protective group can be carried out by protecting piperazinovogo ring in a suitable solvent, such as methylene chloride or chloroform, an appropriate protecting agent, for example, di-tert-butyl bicarbonate, with an appropriate base, for example, triethyleneamine formula IX, where R1represents hydrogen, C1-C6alkyl or C3-C6-cycloalkyl in the compound of formula XV, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, can be carried out by removal of benzyl groups by hydrogenation in the presence of a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, such as acetic acid or ethanol, and the temperature of the reaction mixture from +20oC to +120oC.

(xvi) Halogenoalkane the compounds of formula XV, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl,

< / BR>
Obtaining the compounds of formula XVI can be performed by aromatic electrophilic substitution using a suitable halogenation agent such as VG2, Cl2, I2, ICl or SO2CL2. The reaction can be carried out using the salt or the base compound XV in an appropriate solvent, for example, acetic acid, HCl/ethanol or water, with or without a suitable base, such as alkali metal acetate such as sodium acetate and the reaction can proceed at a pace which represents hydrogen, in the compound of formula XVII,

< / BR>
where Rcrepresents a suitable protective group can be conducted by sewn piperazinovogo ring in a suitable solvent, such as methylene chloride or chloroform, suitable protective agent, for example, di-tert-BUTYLCARBAMATE, with a suitable base, such as triethylamine or2CO3and temperatures from -20oC to +60oC.

(xviii) Halogenoalkane the compounds of formula XVIII, where R9represents a C1-C6-alkoxy, having a form or racemate or enantiomer,

< / BR>
Obtaining the compounds of formula XIX can be performed by aromatic electrophilic substitution using a suitable halogenation agent such as VG2, Cl2, I2, ICl or SO2Cl2. The reaction can be carried out using the salt or the base compound XVIII in an appropriate solvent, for example acetic acid, HCl/ethanol or water, with or without a suitable base, such as alkali metal acetate such as sodium acetate, and the reaction may proceed at temperatures from -20oWith up to room temperature.

< / BR>
(xix) Benzylidene the compounds of formula XIX or Tom, for example benzylchloride, such as benzylbromide or benzylchloride, or active alcohol, such as benzylmethylamine or tosylate. The reaction may be carried out using the salt or the base of the compound XIX in a suitable solvent, for example N,N-dimethylformamide, acetone or acetonitrile with a suitable base, such as triethylamine, NaOH, Panso3or2CO3at a temperature in the range from +20 to +150oC. the Presence of a suitable catalyst, such as alkali metal halide such as potassium iodide or sodium iodide may increase the reaction rate.

< / BR>
(XX) the Conversion of compounds of formula XX to a compound of formula XXI, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, and R9represents a C1-C9-alkoxy, can be carried out by reaction with a compound of formula XXII, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl.

< / BR>
The process can be performed in a suitable solvent, for example in an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide, with the corresponding basis is alistore, such as PdX2, L2Pd(O) or L2PdX2where X represents halogen, such as chlorine or bromine, and L represents a suitable ligand, such as triphenylphosphine, tri-o-tolylphosphino, triphenylphosphine, triphenylarsine or dibenzylideneacetone, and with or without added ligand L', such as triphenylphosphine, tri-o-tolylphosphino, triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (or in the form of a racemate or enantiomer), or triphenylarsine, and the reaction may proceed at temperatures ranging from +20oC to +150oC.

(xxi) the Conversion of compounds of formula XXI in the compound of formula XXIII

< / BR>
where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, R9represents a C1-C6-alkoxy, can be carried out by hydrogenation using a catalyst containing palladium, platinum, rhodium or Nickel in a suitable solvent, such as acetic acid or ethanol, and at a reaction temperature between +20oWith up to 120oC.

(xxii) the Conversion of compounds of formula XXIII, where R1represents hydrogen, the compound of formula XXIV,

< / BR>
where Rcrepresents a protective group, can be osre, with the appropriate protective reagent, such as di-tert-butyl-dicarbonate, with a suitable base, for example, trimethyl-amine or2CO3and at a temperature of from -20oC to +60oC.

(xxiii) Dealkylation of compounds of formula XXI,

< / BR>
obtaining the compounds of formula XXV, where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, can be carried out by treating the compounds with acidic agent, such as HBr, HI, NWG/CH3COOH, VVG3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3WITH6H4S-or2H5S-in a suitable solvent. Suitable solvents can be methylene chloride or chloroform, and the reaction may proceed at temperatures from -78oC to +60oC.

(xxiv) the Conversion of compounds of formula XXV in the compound of formula XXVI

< / BR>
where R1represents hydrogen, C1-C6-alkyl or C3-C6-cycloalkyl, can be carried out by hydrogenation using a catalyst containing palladium, platinum, rhodium or Nickel in a suitable solvent, such as acetic acid or ethanol, and if t is represents a C1-C6-alkyl or C3-C6-cycloalkyl, in the compound of formula XXVII, where R1represents a C1-C6- alkyl or C3-C6-cycloalkyl, can be carried out by exchange reactions of metal-halogen in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether, with suitable alkylate or metal, for example, utility, lithium or magnesium turnings, followed by treatment of the appropriate electrophile such as methyl bromide methyl ether, and subsequent appropriate treatment. The reaction can be carried out at the reaction temperature ranging from -78oWith up to room temperature.

< / BR>
(xxvi) the Conversion of compounds of formula XXVII, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, in the compound of formula XXVIII, where R1represents a C1-C6alkyl or C3-C6-cycloalkyl, can be carried out by removal of benzyl groups by hydrogenation at a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, such as acetic acid and ethanol, and the reaction may proceed at temperatures from +20OOI C1-C6-alkyl or C3-C6-cycloalkyl, to obtain the compounds of formula XXIX, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, can be carried out in a suitable solvent, such as isopropanol or dioxane, a suitable alkylating agent, such as Chlorodifluoromethane in the presence of a suitable base, such as NaOH or KOH at temperatures between +20oC to +80oC.

< / BR>
(xxviii) the Conversion of compound XXIX, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, in the compound of formula XXX, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, can be carried out by removal of benzyl groups by hydrogenation at a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, such as acetic acid and ethanol, and the reaction may proceed at temperatures from +20oC to +120oWITH,

< / BR>
(xxix) the Conversion of compounds XV, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, in the compound of formula XXXI, where Y represents NR2CO., R2is a in the n
-aryl, where aryl represents phenyl or heteroaromatic ring containing one or two heteroatoms selected from N, O and S, and which may be single - or disubstituted R4and/or R5; can be carried out by alkylation of the corresponding activated carboxylic acid such as the acid chloride of the acid, in a suitable solvent, such as methylene chloride or chloroform with a suitable base, such as trialkylamine, such as triethylamine, or by using a carboxylic acid (R3COOH) with an activating agent, such as N,N'-carbonyl diimidazol, N, N'-dicyclohexylcarbodiimide or chloride diphenylphosphine, with a suitable base, such as N-methylmorpholine, in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran and the reaction may proceed at temperatures from +20oC to +150oC.

2. In the case when Y is a CONR2and X represents N

(i) Nitration of compounds of formula XXXII, described by Johnson D. W.; L. N. Mander Aust J. Chem. 1974, 27, 1277-1286, or its racemate or enantiomer, to obtain the compounds of formula XXXIII

< / BR>
where R4represents a C1-C6-alkyl, may be carried out by aromaticus is or nitric acid and sulfuric acid, in a suitable solvent, such as acetic acid, acetic anhydride or water, when the temperature of the reaction mixture from -20oWith up to room temperature.

(ii) Hydrolysis of compounds of formula XXXIII can be carried out under acidic conditions using acids such as H2SO4, HCl, HBr, in a suitable solvent, such as H2Oh, ethanol, methanol, acetic acid or their mixture, and the reaction may proceed at temperatures from +20oWith up to boiling under reflux or under alkaline conditions, using such grounds as NaOH or KOH, in a suitable solvent, such as H2O, ethanol, methanol or mixtures thereof, and the reaction may proceed at temperatures from +20oWith up to boiling under reflux, yielding the compounds of formula XXXIV.

< / BR>
(iii) the Conversion of compounds of formula XXXIV in the compound of formula XXXV, where Y is a CONR2that can be done by activation of the acid function of the compound of formula XXXIV in the form of an acid halide such as acid chloride of the acid with a suitable base, such as trialkylamine, such as triethylamine, or by using an activating agent such as N, N'-carbonyldiimidazole, N,N-DICYCLOHEXYL retele, such as methylene chloride, chloroform, toluene, N,N-dimethylformamide, dioxane or tetrahydrofuran, followed by addition of an appropriate amine or aniline HNR2R3where R2represents N or C1-C6-alkyl, R3represents a C1-C6-alkyl, C3-C6-cycloalkyl or (CH2)n-aryl, where aryl represents phenyl or heteroatom optical ring containing one or two heteroatoms selected from N, O and S, and which may be single - or disubstituted R4and/or R5; and the reaction may proceed at temperatures from 0oC to +120oC.

(iv) the Conversion of compounds of formula XXXV in the compound of formula XXXVI, where Y is a CONR2, R2represents N or C1-C6-alkyl, R3represents a C1-C6-alkyl, C3-C6-cycloalkyl or (CH2)n-aryl, where aryl represents phenyl or heteroaromatic ring containing one or two heteroatoms selected from N, O and S, and which may be single - or disubstituted R4and/or R5; can be done by

< / BR>
hydrogenation using a catalyst containing palladium, platinum or Nickel, UP>C to +120oWith; or restoring dithionite sodium in a suitable solvent.

3. When X represents CH and Y represents NR2CO.,

< / BR>
(i) the Conversion of compounds of formula XXXVII, where R9represents a C1-C6-alkoxy, the compound of formula XXXVIII, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, R9represents a C1-C6-alkoxy, can be prepared by exchange reaction of the metal-halogen in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether, using a suitable alkyl-lithium or metal, for example utility, lithium or magnesium turnings, followed by treatment of the corresponding N-alkylpiperidines, where the alkyl(R1) represents a C1-C6-alkyl or C3-C6-cycloalkyl, such as N-methyl-4-piperidone, with subsequent appropriate treatment. The reaction may be carried out when the temperature of the reaction mixture in the range of from -78oWith up to room temperature.

< / BR>
(ii) a Compound of formula XXXVIII can be converted to a compound of formula XXXIX by treatment with a suitable regenerating agent such as bargersville, such as tetrahydrofuran or diethyl ether. The reaction may be carried out when the temperature of the reaction mixture from 0oWith up to boiling under reflux.

< / BR>
(iii) the Conversion of compounds of formula XXXIX in the compound of formula XL can be carried out by hydrogenation using a catalyst like palladium, platinum, rhodium or Nickel in a suitable solvent, such as acetic acid or ethanol, and the temperature of the reaction mixture from +20oC to +120oC.

4. In the case where Y represents NR2CO and R9is a 6-position

(i) Benzylidene the compounds of formula XLI in the form of its racemate or enantiomer

< / BR>
obtaining the compounds of formula XLII can be carried out by reaction with a suitable Basilisk agent, such as benzylalkonium, such as benzylbromide or benzylchloride, or active alcohol, such as benzylmethylamine or benzalconium. The reaction may be carried out using the salt or the base of the connection XLI in a suitable solvent, for example N,N-dimethylformamide, acetone or acetonitrile with a suitable base, for example NaOH, Panso3TO2CO3or trialkylamines, such as treaties potassium iodide or sodium iodide, can increase the reaction rate.

(ii) Demethylation of compounds of formula XLII

< / BR>
to obtain the compounds of formula XLIII can be carried out by treating the compounds with acidic agent, such as HBr, HI, NWG/CH3COOH, VVG3, AS3, pyridine-Hcl or with a basic nucleophilic agent such as CH3WITH6H4S-or C2H5S-in a suitable solvent. Suitable solvents can be methylene chloride or chloroform, and the reaction may proceed at temperatures from -78oC to +60oC.

< / BR>
(iii) the Conversion of compounds of formula XLIII in the compound of formula XLIV can be done with such a connection, as triftormetilfullerenov anhydride, in a suitable solvent, such as methylene chloride or carbon tetrachloride in the presence of a base such as 2,4,6-kallidin, triethylamine or pyridine, at a temperature of the reaction mixture in the range from -78oWith up to room temperature.

< / BR>
(vi) the Conversion of compounds of formula XLIV in the compound of formula XLV wherein Rdrepresents a C1-C6is an alkyl group, can be carried out in an appropriate solvent, such as dimethylsulfoxide or N,N-dimethylphthalate, such as Pd(OAc)2and a suitable ligand such as triphenylphosphine, 1,1'-bis (diphenylphosphino)ferrocene or 1,3-bis(diphenylphosphino)propane, and a suitable alcohol, such as methanol, ethanol or propanol, in an atmosphere of carbon monoxide at the temperature of the reaction mixture from the 40oWith up to 120oC.

< / BR>
(v) Halogenoalkane the compounds of formula XLV wherein Rdrepresents a C1-C6is an alkyl group, to obtain compounds of formula XLVI can be carried out using a suitable halogenation agent such as 1,3-dibromo-5,5-dimethylhydantoin. The reaction can be carried out using the salt or the base of the connection XLV in an appropriate solvent, such as CF3SO3H or H2SO4and when the temperature of the reaction mixture from the 30oWith up to 150oWITH

< / BR>
(vi) the Conversion of compounds of formula XLVI in the compound of formula XLVII, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, can be performed by reaction with a compound of formula XXII, where R1represents a C1-C6-alkyl or C3-C6-cycloalkyl.

< / BR>
The process can be carried out in a suitable solvent, for example apretando the tion, such as tert-piperonyl or sodium bis(trimethylsilyl)amide lithium, in the presence of a suitable palladium catalyst, such as d2, L2Pd(O) or L2PdX2where X represents halogen, such as chlorine or bromine, and L represents a suitable ligand, such as triphenylphosphine, tri-o-tolylphosphino, triphenylphosphine, triphenylarsine or dibenzylideneacetone, and with or without added ligand L', such as triphenylphosphine, tri-o-tolylphosphino, triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (or in the form of a racemate or enantiomer) or triphenylarsine, and the reaction can be carried out at a temperature of from +20oC to +150oC.

< / BR>
(vii) the Conversion of compounds of formula XLVII in the compound of formula XLVIII can be done by restoring Olkiluoto of ester in a suitable solvent, such as diethyl ether or tetrahydrofuran, corresponding regenerating agent such as alumalite lithium, and the reaction may proceed at temperatures from +20oWith up to boiling under reflux, followed by removal of benzyl groups and recovery of benzyl alcohol by hydrogenation at a suitable catalyst containing palladium, rhodium, platinum, and is the temperature from +20oC to +120oC.

(viii) a Compound of formula XLVIII can also be obtained by protecting the amino groups of the compounds of formula XVIII, or its racemate or enantiomer,

< / BR>
to obtain the compounds of formula XLIX by reaction with a suitable allermuir agent, such as triperoxonane chloride or triperoxonane anhydrit. The reaction can be carried out using the salt or the base compound XVIII in a suitable solvent, such as methylene chloride or chloroform with a suitable base, for example NaOH, Panso3TO2CO3or trialkylamines, such as triethylamine, at temperatures between -20oC to +80oC.

(ix) the Nitration of compounds of formula XLIX

< / BR>
to obtain the compounds of formula L can be made by treating compounds suitable nitrious agent such as nitric acid, in a suitable solvent, such as acetic acid, and the reaction may proceed at temperatures from 0oC to +30oC.

< / BR>
(x) Halogenoalkane the compounds of formula L to obtain the compounds of formula LI can be carried out with a suitable halogenation agent such as N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin. The reaction of her acid, for example, CF3SO3H or H2SO4and when the temperature of the reaction mixture from 0oC to +80oC.

< / BR>
(xi) Making connections. formula LI in the compound of formula LII can be carried out by

a) hydrolysis of the amide in the compound of formula LI in acidic conditions using acids such as H2SO4, HCl or NVG, in a suitable solvent, such as H2Oh, ethanol, methanol or mixtures thereof, and the reaction may proceed at temperatures from +20oC to +100oWith, or in alkaline medium using such bases as NaOH or KOH, in a suitable solvent, such as H2Oh, ethanol, methanol or mixtures thereof, and the reaction may proceed at temperatures from +20oC to +100oC.

For hydrolysis should

b) benzylidene primary amine by reaction with a suitable Basilisk agent, such as benzylalkonium, such as benzylbromide or benzylchloride, or active alcohol, such as benzylmethylamine or benzalconium. The reaction can be carried out in a suitable solvent, for example N, N-dimethylformamide, acetone or acetonitrile with a suitable base, for example NaOH, Panso3TO2CO3or three-alkylamino, the e formula LII. The presence of a suitable catalyst, such as potassium iodide or sodium iodide may increase the reaction rate.

(xii) the reduction of compound of formula LII to obtain the compounds of formula LIII can be carried out in a suitable solvent, such as methanol/water or ethanol/water, in the presence of a suitable reducing agent, such as hydrosulfite sodium, when the temperature of the reaction mixture from +20oC to +100oC.

< / BR>
(xiii) the Conversion of compounds of formula LIII in the compound of formula LIV

< / BR>
can be performed by reaction with a compound of formula XI

< / BR>
where X represents a removable group, for example halogen, such as chlorine or bromine, or an alkane - or arenesulfonyl group, such as pair-toluensulfonate group, and R1represents a C1-C6-alkyl or C3-C6-cycloalkyl. The process can be carried out in a suitable solvent, such as ethanol, butanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base, such as2CO3, Panso3or KOH, and the reaction may proceed at temperatures from +20oC to +150oC.

< / BR>
(xiv) the Transformation of the who SUB>6
-cycloalkyl, R9represents a C1-C6-alkyl, may be carried out by the exchange reaction of the metal-halogen in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether, using a suitable alkyl-lithium or metal, for example, utility, lithium or magnesium turnings, followed by treatment of the corresponding alkylhalogenide, such as methyliodide, ethylbromide or propyliodide, and the reaction may be conducted at temperatures ranging from -78oWith up to room temperature, or by treatment with other electrophiles, such as acetaldehyde or methylchloroform, and subsequent appropriate treatment. The reaction can be carried out at the temperature of the reaction mixture in the range from -78oWith up to room temperature.

When as electrophile acetaldehyde is used for the above reactions should restore gasoline alcohol by hydrogenation at a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, such as acetic acid or ethanol, and the reaction may proceed at temperatures from +20oC to +120oC.

When in cacuso ether in a suitable solvent, such as diethyl ether or tetrahydrofuran, using an appropriate reducing agent, such as alumalite lithium and the reaction may occur at temperatures from +20oWith up to boiling under reflux, followed by recovery of gasoline alcohol by hydrogenation at a suitable catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, such as acetic acid or ethanol, and the reaction proceeds at temperatures from +20oC to +120oC.

< / BR>
(xv) Demethylation of compounds of formula LV to obtain the compounds of formula LVI can be carried out by treating compound acidic agent such as an aqueous solution of HBr, HI, NWG/CH3COOH, VVG3, AS3, pyridine-HCl or with a basic nucleophilic agent such as CH3WITH6H4S-or2H5S-in a suitable solvent. Suitable solvents can be methylene chloride or chloroform, and the reaction may proceed at temperatures from -78oC to +60oC.

< / BR>
(xvi) Transformation of compounds of formula LVI in the compound of formula LVII can be carried out by processing in this connection, as triftoratsetofenona, such as 2,4,6-kallidin, triethylamine or pyridine, at a temperature of the reaction mixture in the range from -78oWith up to room temperature.

< / BR>
(xvii) the Conversion of compounds of formula LVII in the compound of formula XLVIII can be carried out

a) by treating the compounds of formula LVII appropriate palladium catalyst, such as palladium(II) acetate, and the appropriate ligand, such as triphenyl-phosphine, in the presence of a suitable acid, for example formic acid, in an appropriate solvent such as N,N-dimethylformamide, at a temperature of the reaction mixture from +20oC to +120oS, followed

b) by reaction in a suitable solvent, such as methanol, in the presence of ammonium formate and Pd/C, when the temperature of the reaction mixture in the range from +20oWith up to boiling under reflux with the obtained compounds of formula XLVIII.

Methods of obtaining the final products

Another objective of the present invention is a method A(i), A(ii), or to obtain compounds of General formula I by

A(i)

acylation, in the case when R1represents a C1-C6-alkyl or C3-C6-cycloalkyl, Y represents NR2CO., Rwhat ucheniem cases when R9is a Deputy, they are sensitive to certain allermuir agents, the compounds of formula A,

< / BR>
the activated carboxylic acid R3L, when L represents a removable group, or carboxylic acid R3COOH with an activating agent.

Thus, the acylation in accordance with method A(i) can be carried out with the appropriate activated carboxylic acid, R3L, where R3such as defined above, and L represents a removable group, such as halogen, for example chlorine, in a suitable solvent, such as methylene chloride or chloroform with a suitable base, such as trialkylamine, such as triethylamine, at a temperature of from -20oWith up to boiling under reflux, or carboxylic acid R3COOH, where R3such as defined above, with an activating agent, such as N/N'-carbonyl diimidazol, N,N'-dicyclohexylcarbodiimide or chloride diphenylphosphine, with a suitable base, such as N-methylmorpholine, in a suitable solvent such as N,N-dimethylformamide or Tetra-hydrofuran, and the reaction can bsty carried out at a temperature of from +20oC to +150oC.

A(ii) represents hydrogen, Rcrepresents a protective group, and X, R3and R9such as defined above for General formula I, except that R9is a Deputy who is sensitive to certain allermuir agents, the compounds of formula

< / BR>
the activated carboxylic acid R3COL, where L represents a removable group, or carboxylic acid R3COOH with an activating agent, followed by removal of the protective group Rc.

Thus, the acylation according to the process A(ii) can be performed with the appropriate activated carboxylic acid, R3L, where R3such as defined above, and L represents a removable group, such as halogen, for example chlorine, in a suitable solvent, such as methylene chloride or chloroform with a suitable base, such as trialkylamine, such as triethylamine, at a temperature of from -20oWith up to boiling under reflux, or carboxylic acid R3COOH, where R3such as defined above, with an activating agent, such as N,N'-carbonyl diimidazol, N,N'-dicyclohexylcarbodiimide or chloride diphenylphosphine, with a suitable base, t is ia can be carried out at a temperature of from +20oC to +150oWith the subsequent removal of the protective group Rcby hydrolysis in a suitable solvent, such as methylene chloride or chloroform with a suitable acid, such as triperoxonane acid, at a temperature of from +20oC to +60oC.

Century

the reaction, in the case when Y is a CONR2, R2, R3and R9such as defined above for General formula I, except that R9is a Deputy, which is sensitive to a specific alkylating agent XI, compounds of the formula

< / BR>
with the compound of the formula XI, where X represents a group to delete.

Thus, the reaction according to the method can be performed with the compound of the formula XI, where R1such as defined above for General formula I, and X represents a removable group, for example halogen, such as chlorine or bromine, or an alkane - or arenesulfonyl group, such as pair-toluensulfonate group. The process can be carried out in a suitable solvent, such as ethanol, butanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with or without a suitable base, such as2CO3, NaHCO3or CON,beam, when Y represents NR2CO., R9represents halogen, and R1, R2and R3such as defined above for General formula I, the compounds of formula D

< / BR>
with a suitable halogenation agent such as Br2, Cl2, I2, ICl or SO2Cl2.

Thus, the reaction in accordance with the method may be performed by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, CL2, I2, ICl or SO2CL2. The reaction can be carried out using the salt or the base of the connection D in an appropriate solvent, for example acetic acid, HCl/ethanol or water, with or without a suitable base, such as alkali metal acetate such as sodium acetate, and the temperature of the reaction mixture from -20oWith up to room temperature.

Intermediate substance

Another aspect of the invention is a compound having the formula

< / BR>
where X represents N or CH;

Z represents NH2or COOH;

R1represents H, C1-C6-alkyl or C3-C6-cycloalkyl;

R9is the>
HE, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N or O, where the substituent(s) is(are) a C1-C6-alkyl; go COR8; where

R6represents H, C1-C6-alkyl or C3-C6-cycloalkyl;

R7represents a C1-C6-alkyl or C3-C6-cycloalkyl; and

R8represents a C1-C6-alkyl, C3-C6-cycloalkyl, CF3, NR6R7, phenyl, heteroaromatic ring containing one or two heteroatoms selected from N, O or S, or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2where R6and R7such as defined above,

and

< / BR>
where Y represents CONR2where R2represents a C1-C6-alkyl,

R3represents a C1-C6-alkyl, C3-C6-cycloalkyl or (CH2)n-aryl,

where aryl is subimage to be one - or disubstituted R4and/or R5; where R4, R5and n are such as defined above;

R9represents a C1-C6-alkyl, C3-C6-cycloalkyl, F3, OCHF2, OCH2F, halogen, CN, CF3HE, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N or O, where the substituent(s) is(are) a C1-C6-alkyl; or COR8; where R6, R7and R8such as defined above.

Working examples

The following examples reveal, but do not limit the invention.

Example 1

(R)-2-N,N-dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalen

To a solution of (R)-8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (24 g, 0.11 mol) in acetonitrile (600 ml) is added potassium carbonate (53 g, to 0.39 mol), potassium iodide (catalytic amount) and benzylbromide (34 ml, 0.28 mol). The reaction mixture is stirred at the boil under reflux for 35 hours.

After filtering off the precipitate and removal of Aceto the UB>2SO4) and evaporated in vacuum to give crude product which is purified on a column of silica gel using hexane/ethyl acetate (3:1) as eluent. Yield: 36 g (91%) named the title compound as white solid: etc., 105-107oC; []21d+124(C 1.0, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 357 (100, M+).

Example 2

(R)-7-N,N-dibenzylamino-5,6,1,8-tetrahydro-1-naphthol

(R)-2-N,N-dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalen (43 g, 0.12 mol) is dissolved in diethyl ether (800 ml) and added dropwise an excess of ethereal Hcl solution. The precipitate is filtered off and dried in vacuum, obtaining a white solid. This crude product (42 g, 0.11 mol) is dissolved in anhydrous methylene chloride (1 l) and cooled to -60oC. To this solution is added dropwise tribromide boron (16 ml, 0.15 mol), dissolved in anhydrous methylene chloride (100 ml). The temperature of the reaction solution was adjusted to -5oWith and support throughout the night. To this solution was cooled with ice, added dropwise a 2 M aqueous solution of ammonium hydroxide and the mixture extracted twice methylenchloride. The combined organic phases are dried (Na2SO4), filtered and rest the AET 34 g (yield 93%) named the title compound as a thick clear oil: []21d+118(1.5; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 343 (53, M+).

Example 3

(R)-2-(7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy)-2-methylpropanamide

(R)-2-N,N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (10 g, 29 mmol) stirred in anhydrous dioxane (150 ml) with sodium hydride (80% in oil, 0.96 g, 32 mmol) over 1 hour. Add 2-bromo-2-methylpropanamide (4.8 g, 29 mmol; described in: Coutts, I. G. S.; Southcott, M. R. J. Chem. Soc. Perkin Trans. I, 1990, 767-770) and the reaction mixture is heated at 100oC for 2.5 hours. After cooling, the precipitated sodium bromide is filtered off, the filtrate is evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic phase is separated, dried (Na2SO4), filtered and evaporated, to give crude product which is purified on a column of silica gel using methylene chloride as eluent. Yield: 9.6 g (76%) named the title compound as white crystals: I. ii. 125-126oC; []21d+98(1,1; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 428 (13, M+).

Example 4

(R)-N-(7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-2-hydroxy-2-methylpropanamide

To a solution of (R)-2-(who rehydro-2(H)-pyrimidone (10 ml) and dry N,N-dimethylformamide (100 ml) is added sodium hydride (80% in oil, 1.4 g, 47 mmol) and the reaction solution is heated at 130oC for 8 hours. The solution is poured into a mixture of ice and water and extracted three times with ethyl acetate. The combined organic phase is dried (Na2SO4), filtered and evaporated in vacuum. After chromatography on silica gel (eluent: chloroform/ethanol saturated NH3; 100:0.5 to) obtain 7.6 g (yield 84%) named the title compound as white crystals: I. p. 134-135oC; []21d+130(1,1; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 428 (1, M+).

Example 5

(R)-2-N,N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalen

(R)-N-(7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-2-hydroxy-2-methylpropionamide (7,4 g, 17 mmol) dissolved in a mixture of ethanol (200 ml) and 20% aqueous Hcl solution (300 ml) and heated to boiling under reflux for 8 hours. The ethanol is evaporated in vacuo, the remaining solution was washed twice with diethyl ether and cooled in an ice bath. After alkalizing 45% aqueous solution of sodium hydroxide, the mixture extracted with methylene chloride. The combined organic phase is dried (Na2SO4), filtered and evaporated in vacuum. Purification on a column of silica gel with ISO-brown oil:

[]21d+124(from 0.9; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 342 (92, M+).

Example 6

(R)-1-(7-N, N-dibenzylamino-5,6,7,8-tetracera-1-naphthyl)-4-N-methylpiperazine-2,6-dione

1,1'-carbonyldiimidazole (6.0 g, 37 mmol) is added to a stirred suspension methyliminodiacetic acid (2.7 g, 18 mmol) in anhydrous tetrahydrofuran (250 ml). The reaction mixture is heated to boiling under reflux for 1.5 hours. Add (R)-2-N,N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalen (5.7 g, 17 mmol) and stirring while boiling under reflux continued for 17 hours. Pay an additional amount of 1,1'-carbonyldiimidazole (2.9 g, 18 mmol) and heated to boiling under reflux for a further 17 hours. The solvent is evaporated in vacuum and the crude product is purified on a column of silica gel using chloroform/ethanol saturated NH3(100 level:0.5) as eluent. Yield: 6.6 g (87%) named the title compound as an oil: []21D+90(0,52; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 453 (8, M+).

Example 7

(R)-2-N, N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-Tetra is given to a suspension of lithium aluminum hydride (0,57 g, 15 mmol) in anhydrous diethyl ether (70 ml). The reaction mixture is heated to boiling under reflux for 7 hours. The reaction is quenched by addition of water (0,60 ml), 15% aqueous sodium hydroxide solution (0,60 ml) and again water (1.8 ml). The mixture is filtered, dried (Na2SO4) and evaporated in vacuo. Purification on a column of silica gel using chloroform/ethanol saturated NH3, (100:2) as eluent gives 1.0 g (yield 79%) named the title compound as a thick oil: []21D+53(0.5; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 425 (2, M+).

Example 8

(R)-5-bromo-2-N, N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1, 2,3,4-tetrahydronaphthalen

To a solution of (R)-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (2.8 g, 6.5 mmol) and sodium acetate (6.8 g, 83 mmol) in acetic acid (100 ml) is added bromine (370 ml, 7.2 mmol) in one portion and the reaction mixture is stirred for 5 minutes. The solvent is evaporated in vacuo, the remaining solid is partitioned between water and methylene chloride and cooled in an ice bath. The aqueous phase is alkalinized 2M aqueous solution of sodium hydroxide and the phases are separated. The organic phase sushi is images using chloroform/ethanol, saturated NH3(100: 2) as eluate. Yield: 2 g (61%) of a thick brown oil: EIMS (70 electrovolt) m/z (relative intensity) 503 and 505 (0.6 M+).

Example 9

(R)-2-N, N-dibenzylamino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

To a solution of (R)-2-N, N-dibenzylamino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (2.1 g, 4.7 mmol) in acetic acid (40 ml) was added 47% aqueous solution of Hydrobromic acid (20 ml) and the reaction solution heated to boiling under reflux for 7 hours. The solvent is evaporated in vacuum and the residue is dissolved in water (75 ml) and cooled in an ice bath. The solution is alkalinized 2M aqueous solution of sodium hydroxide and extracted with methylene chloride. The phases are separated and the organic phase is dried (Na2SO4), filtered and evaporated in vacuum. Purification on a column of silica gel using chloroform/methanol/concentrated ammonium hydroxide (95: 5: 0.5 to) as the eluent gives 1.8 g (yield 89%) named the title compound as a thick oil: EIMS (70 electrovolt) m/z (relative intensity) 441 (7 M+).

Example 10

(R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahedronal who mmol) and ammonium formate (2.4 g, 38 mmol) in methanol (50 ml) is added palladium (10%) on charcoal. The mixture is heated at the boil under reflux for 4 hours and then palladium is filtered off. The solvent is evaporated in vacuo, the residue partitioned between diethyl ether and 2M ammonium hydroxide. The organic phase is separated, dried (Na2SO4), filtered and evaporated in vacuum. The residue is washed with water and diethyl ether and then dried in vacuum. Yield: 200 mg (44%) of gray crystals: I. ii. 238-239oC; []21d+43(c=0.5; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 261 (65 M+).

Example 11

(R)-N-[5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-Tetra-hydro-2-naphthyl]-4-butoxybenzene

It chilled with ice to a solution of (R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.38 mmol) and triethylamine (79 μl, or 0.57 mmol) in N,N-dimethylformamide (30 ml) is added dropwise 4-butoxybenzoate in N,N-dimethylformamide (5 ml). After the addition, the reaction mixture was stirred at ambient temperature for 15 minutes. The solvent is evaporated in vacuo and the residue purified on a column of silica gel, using as eluent chloroform/methanol/conc is []21D-20(C=0,25; chloroform); EIMS (70 electrovolt) m/z (relative intensity) 437 (16 M+).

Example 12

(R)-2-N,N-dibenzylamino-8-(piperazine-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalen (9,8 g, 39 mmol) and bis(2-chloroethyl)amine hydrochloride (5.5 g, 32 mmol) is dissolved in n-butanol (80 ml). The reaction mixture was stirred at 100oWith 65 hours, filtered, the solvent is evaporated in vacuum. Purification on a column of silica gel, using as eluent chloroform/methanol/concentrated ammonium hydroxide (95: 5: 0.5) with gives 6.0 g (yield: 51%) named the title compound as a thick oil: []21D+72(C= 1.0 in chloroform); EIMS (70 electrovolt) m/z (relative intensity) 411 (2 M+).

Example 13

(R)-2-amino-8-(piperazine-1-yl)-1,2,3,4-tetrahydronaphthalen

To a solution of (R)-2-N, N-dibenzylamino-8-(piperazine-1-ID)-1,2,3,4-tetrahydronaphthalene (5.5 g, 13 mmol) in methanol (400 ml) is added ammonium formate (20 g, 0.32 mol) and palladium (10%) on charcoal. The mixture is refluxed for 1 hour and then palladium is filtered off. The solvent is evaporated in vacuum and the residue is distributed is), filtered and evaporated in vacuum to give crude product which is purified on a column of silica gel, using as eluent chloroform/methanol/concentrated ammonium hydroxide (80:20:2,5). Yield: 2.4 g (76%) named the title compound as an oil: []21D+9,9(C=1.0 in chloroform); EIMS (70 electrovolt) m/z (relative intensity) 231 (24 M+).

Example 14

(R)-2-amino-5-bromo-8-(piperazine-1-yl)-1,2,3,4 - tetrahydronaphthalen

Named the title compound is obtained from (R)-2-amino-8-(piperazine-1-yl)-1,2,3,4-tetrahydronaphthalene, following the General method of example 8. Purification on a column of silica gel, using as elution solvent of methylene chloride/ethanol/concentrated ammonium hydroxide (80:20:2) to give 0.8 g (67%) with a dense light brown oil: []21Dis 6.2(C=1.0 in chloroform); EIMS (70 electrovolt) m/z (relative intensity) 309 m 311 (3.5 M+).

Example 15

Tert-butyl (R)-4-(7-amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylate

To a cooled on ice to a solution of (R)-2-amino-5-bromo-8-(piperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (0.8 g, 2.6 mmol) and triethylamine (of 0.53 ml, 3.9 mmol) in methylene chloride (50 ml) is added di-tert-buildi remediates at room temperature for 1 hour. Add water (10 ml) and the mixture is cooled in a bath with ice. The aqueous phase is alkalinized 2M aqueous solution of sodium hydroxide and the phases are separated. The organic phase is dried (Na2SO4), filtered and evaporated in vacuum to give crude product which is purified on a column of silica gel, using as eluent chloroform/methanol/concentrated ammonium hydroxide (95: 5: 0.5 to). Output: 0,41 g (38%) as a thick colorless oil: []21D+13(C=1 in chloroform); EIMS (70 electrovolt) m/z (relative intensity) 409 and 411 (75, M+).

Example 16

(R)-N-[5-bromo-8-(4-tert-butoxycarbonylmethyl-1-yl)-1,2, 3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

4-morpholinomethyl acid (0.50 g, 2.4 mmol; described in Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) dissolved in thionyl chloride (10 ml). After about 2 minutes tindharia is evaporated in vacuo, the residue treated with toluene and the solvent again evaporated in vacuo. The crude acid chloride acid (81 mg, 0.36 mmol) dissolved in methylene chloride (10 ml) and added dropwise to a solution of tert-butyl (R)-4-(7-amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl)piperazine-1-carboxylate (140 mg, 0.34 mmol) and triethylamine (71 μl, 0.51 mmol) in methylene chloride (10 ml). After a diluted aqueous sodium hydrogen carbonate solution and the phases are separated. The organic phase is dried (Na2SO4), filtered and evaporated in vacuo, the residue is purified on a column of silica gel, using as eluent chloroform/ethanol saturated NH3(100:2). Yield: 160 mg (79%) of a thick colorless oil: []21D-11(C=1, chloroform); TSP MC m/z (relative intensity) 599 and 601 (35M++1).

Example 17

(R)-N-[5-bromo-8-(piperazine-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

It chilled with ice to a solution of (R)-N-[5-bromo-8-(4-tert-butyloxycarbonyl-1-yl)-1,2,3,4-tetrahydro-2 - naphthyl] -4-morpholinomethyl (150 mg, 0.26 mmol) in methylene chloride (20 ml) is added triperoxonane acid (0.7 ml). The reaction mixture was stirred at ambient temperature for 20 hours. The solvent is evaporated in vacuum, the residue is dissolved in water (20 ml), alkalinized 2M aqueous solution of sodium hydroxide and extracted with methylene chloride. The phases are separated, the organic phase is dried (Na2SO4), filtered and evaporated in vacuum. The residue is purified on a column of silica gel, using as eluent chloroform/methanol/concentrated ammonium hydroxide (90: 10: 1). Yield: 94 mg (72%) of white crystals: I. p. 228-229oC; []21Dptx2">

Example 18

(R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

To a solution of (R)-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (4.0 g, 9.4 mmol) in methanol (250 ml) is added ammonium formate (14 g, 56 mmol) and palladium (10%) on activated carbon (1.4 g). The mixture is refluxed for 3 hours, then palladium is filtered off. The solvent is evaporated in vacuum, the residue is distributed between methylene chloride and 2M ammonium hydroxide solution. The organic phase is separated, dried (Na2SO4), filtered and evaporated in vacuum, obtaining the crude product, which was purified on a column of silica gel using as eluent chloroform/methanol/concentrated ammonium hydroxide (90:9: 0.5) is. Output: 1.9 mg (83%) oil: []21D-2,7(C=1.0 in chloroform); EIMS (70 electrovolt) m/z (relative intensity) 245 (5, M+).

Example 19

(R)-2-amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

Named the title compound is obtained from (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene using the General method of example 8. Purification on a column of silica gel using as eluent chloroform/ethanol/is before) m/z (relative intensity) 323 and 325 (20, M+).

Example 20

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

Named the title compound is obtained from (R)-2-amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene using the General method of example 16. Purification on a column of silica gel using as eluent chloroform/methanol/concentrated ammonium hydroxide (95:5:1) to give 100 mg (yield 62%) of white crystals: I. ii. 245-246oC C[]21D-23(C=1, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 512 and 514 (1, M+).

Example 21

(R)-2-amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride

(R)-2-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (5.0 g, 23 mmol) is dissolved in acetic acid (300 ml) under nitrogen atmosphere. Add sodium acetate (5.5 g, 70 mmol), then one portion add bromine (3.5 g, 23 mmol). The mixture is stirred for 5 minutes at room temperature. The solvent is removed in vacuum, the residue is distributed between ethyl acetate and NaOH (2M). The layers separated, the aqueous phase is extracted twice with ethyl acetate. The organic layers are combined and dried (Na2SO4). The solvent is removed in vacuum, obtaining a residue in the p (3M): Yield: 7.7 g (94%). Recrystallization from methanol gives named in the title compound in the form of needle-shaped crystals: I. ii. 264-265oC; []21D+54(C=1, Meon); EIMS (70 electrovolt) m/z (relative intensity) 257 (30 M+,81VG), 255 (31, M+,79Br).

Example 22

(R)-8-bromo-2-N,N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalen

(R)-2-amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (4.5 g, 17.5 mmol), benzylbromide (6.6 g, 38 mmol), potassium carbonate (9.7 g, 70 mmol) and potassium iodide (100 mg, catalytic amount) was stirred with acetonitrile (250 ml) under nitrogen atmosphere and refluxed for 18 hours. The solvent is removed in vacuo and the residue distributed between ethyl acetate and ammonia (2M). The layers separated, the organic layer is dried (MgSO4). The solvent is removed in vacuum, obtaining a residue, which is purified using flash chromatography on silica gel, using as eluent hexane/methylene chloride 8:2. Named in the title compound obtained as oil. Yield 7.5 g (98%): []21D+87(C=1, Meon); EIMS (70 electrovolt) m/z (relative intensity) 437 (12 M+,81VG), 435 (13, M+,79Br).

Example 23

(R)-2-N, N-Domino-5-methoxy-1,2,3,4-tetrahydronaphthalene (19 g, 44 mmol) in dry toluene (500 ml) in an argon atmosphere add N-methylpiperazine (5,9 ml, 53 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0,41 g, 0.44 mmol), (R)-BINAP (0,82 g, 1.3 mmol) and tert-piperonyl sodium (0,40 mg, 4.2 mmol). The dark solution was stirred at 85oC for 23 hours and then cooled, filtered and evaporated in vacuum. Purification on a column of silica gel using as eluent chloroform/ethanol saturated NH3(100:2) to give 19 g (97%) of a thick colorless oil: []21D+72(C=1, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 455 (15, M+).

Example 24

(R)-2-amino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tet-raidernation

Named the title compound is obtained from (R)-2-N,N-dibenzylamino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene, following the General method of example 10. Output: 5.3v g (82%) of a thick colorless oil: []21D+20(C=chloroform 1,1); EIMS (70 electrovolt) m/z (relative intensity) 275 (53, M+).

Example 25

(R)-N-[5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

To a solution of 4-morpholinomethyl acid (0,92 g, 4.5 mmol; described in: Degutis, J. ; Rasteikiene, 4.8 mmol) and the reaction mixture is heated at 75oC. When the emissions of carbon dioxide ends (after 45 minutes), the reaction mixture is cooled to room temperature, add a solution of (R)-2-amino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (1.2 g, 4.2 mmol) dissolved in anhydrous N,N-dimethylformamide (20 ml). The reaction mixture was allowed to mix at ambient temperature for 48 hours, the solvent is evaporated in vacuum. Purification on a column of silica gel using as eluent chloroform/methanol/concatinating ammonium hydroxide (180:5:0,5) followed by recrystallization from ethyl acetate and a few drops of methanol gives 1.0 g (53%) of white crystals: I. ii. 237-238o[]21D-40(c=l, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 464 (5, M+).

Example 26

(R)-N-[5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-cyanobenzene

Named the title compound is obtained from (R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene, following the General process for the preparation of example 11. Purification on a column of silica gel using as eluent chloroform/methanol/concatinating ammonium hydroxide (95: 5: 0.5 to) give 71 mg of anal); EIMS (70 electrovolt) m/z (relative intensity) 390 (12, M+).

Example 27

(R)-N-[5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinosydnonimine

Named the title compound is obtained from (R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene, following the General process for the preparation of example 16. Purification on a column of silica gel using as eluent chloroform/methanol/concatinating ammonium hydroxide (96:4:0,3) after recrystallization from ethyl acetate/diethyl ether to give 93 mg (yield 52%) of white crystals: I. p. 209-210o[]21D-18(C=1, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 492 (36, M+).

Example 28

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinosydnonimine

Named the title compound is obtained from (R)-2-amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene, following the General process for the preparation of example 16. Purification on a column of silica gel using as eluent chloroform/methanol/concentrated ammonium hydroxide (96: 4: 0,3) after recrystallization from ethyl acetate/diethyl ether to give 110 mg (o m/z (relative intensity) 540 and 542 (32, M+).

Example 29

Methyl 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxylate

Methyl 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylate (1.1 g, 5 mmol; described in: Johnson, D. W.; Manger, L,N, Aust. J. Chem. 1974, 8, 1277-1286) is dissolved in acetic acid (20 ml), treated with 70% nitric acid (0.4 ml) at 0oC for 1 hour and the mixture is poured into ice water and diethyl ether. The organic phase is separated, evaporated in vacuo and the residue triturated with diisopropyl ether, receiving 0.27 g (20%) named in the title compound in the form of crystals: I. ii. 100-104oWith; EIMS (70 electrovolt) m/z (relative intensity) 265 (35, M+).

Example 30

5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid

A mixture of methyl 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxylate (1.9 g, 7.1 mmol) in methanol (20 ml) and 2M NaOH (10 ml) is refluxed for 1.5 hours and the solvent is evaporated in vacuum. The residue is placed in ethyl acetate and acidified with. The organic phase is separated, dried and evaporated in vacuum, obtaining 1.7 g (yield 95%) of crystals: etc. (after recrystallization in disapproval ether/ethanol) 189-190oWith; EIMS (70 electrovolt) m/z (relative intensity) 251 (30, M+).

Example 32

N-(4-morpholinyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamid

A solution of N-(4-morpholinomethyl)-5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxamide (of 2.05 g, 5 mmol) and dithionite sodium (3.5 g, 20 mmol) in N, N-dimethylformamide (20 ml) and water (2 ml) is heated at 90owithin 7 hours. After cooling, the reaction mixture is distributed between water and ethyl acetate, the phases are separated, the organic phase is washed twice with water and evaporated in vacuum. The residue is triturated with diisopropyl ether/ethyl acetate, gaining 1.4 g (yield 72%) named the title product in the form of crystals: I. ii. 219-222oWith; EIMS (70 electrovolt) m/z (relative intensivepromotion-2-carboxamid

A solution of N-(4-morpholinyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide (1.4 g, 3.5 mmol), bis(2-chloroethyl)-methylamine hydrochloride (960 mg, 5 mmol) and sodium bicarbonate (420 mg, 5 mmol) in n-butanol (30 ml) is heated at 90owithin 5 hours. After cooling, add 2M ammonium hydroxide (30 ml) and the mixture is heated at 50oC for 1 hour. The phases are separated, evaporated in vacuo and purified using flash chromatography on silica gel with chloroform/ethanol/conc. the ammonium hydroxide 90/10/0,3 as eluent. Yield: 320 mg (20%) named in the title compounds, etc., 230-232oWith; EIMS (70 electrovolt) m/z (relative intensity) 464 (75, M+).

Example 34

N-(4-morpholinomethyl)-5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxamid

A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (1.0 g, 4 mmol), toluene (20 ml), N,N-dimethylformamide (10 drops) and thionyl chloride {1.5 ml, 20 mmol) is heated at 60oC for 1 hour. The solvent is removed in vacuo and the residue dissolved in methylene chloride (20 ml), added to a solution of 4-aminobenzonitrile (820 mg, 4 mmol, described in: Devlin J. P. J. Chem. Soc. Perkin Trans. I, 1975, 830-841) and triethylamine (800 mg, 8 mmol) in methylene chloride (30 Aut, dried, the solvent is removed in vacuum. The oily residue is crystallized from disapproval ether/ethyl acetate, receiving 1.2 g (yield 73%) named in the title compound in the form of crystals: I. ii. 186-189oWith; EIMS (70 electrovolt) m/z (relative intensity) 439 (20, M+).

Example 35

N-(morpholinoethyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamid

A solution of N-(4-morpholinomethyl)-5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxamide (1.3 g, 2.8 mmol) and dithionite sodium (2.0 g, 11 mmol) in N,N-dimethylformamide (20 ml) and water (2.5 ml) is heated at 85owithin 3 hours. After cooling, the reaction mixture is distributed between water and ethyl acetate, the phases are separated and the organic phase is washed twice with water and evaporated in vacuum. The organic phase is dried and evaporated. The residue is treated diisopropyl ether, receiving 310 mg (yield 30%) named in the title compound in the form of crystals: EIMS (70 electrovolt) m/z (relative intensity) 409 (100, M+).

Example 36

N-(morpholinoethyl)-8-(4-methylpiperazin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamid

A solution of N-(morpholinoethyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-mg, 1.0 mmol) in n-butanol (20 ml) is heated at 90owithin 5 hours. After cooling, add 2M ammonium hydroxide (10 ml) and the mixture is heated at 50oC for 1 hour. The organic phase is evaporated in vacuum, the residue is purified using flash chromatography on a column of silica gel, using as eluent chloroform/ethanol/ammonium hydroxide (90;10:0.5), the receiving 60 mg (18%) named in the header connection: EIMS (70 electrovolt) m/z (relative intensity) 492 (50, M+).

Example 37

(R)-2-amino-5-methoxy-8-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalen

(R)-8-bromo-2-N,N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalen (6.8 g, 16 mmol) dissolved in anhydrous tetrahydrofuran (100 ml) under nitrogen atmosphere. The solution is cooled to -78oC and added dropwise n-utility (11.7 ml, 1.6 M, 19 mmol) for 3 minutes. The mixture is stirred for 5 minutes and N-methyl-4-piperidone (5,4 g, 48 mmol) is added dropwise within 3 minutes. Remove the cooling bath, allow the temperature to rise to 0oWith, and then the reaction quenched by addition of water. The layers separated, the organic layer is dried (MgSO4). The solvent is removed in vacuum, obtaining a residue, which is purified by crystallization (ethyl acetate/hexane). Yield 5.8 g (77%): EIMS (70 e which are pair-toluensulfonate acid (2.8 g, 15 mmol) and the reaction mixture is stirred at the boil under reflux for 8 hours under nitrogen with azeotropic distillation of the water in the nozzle Dean-stark. The cooled reaction mixture was washed with 2M aqueous sodium hydroxide solution, the phases are separated, dried (MgSO4), filtered and evaporated in vacuum, obtaining a thick oil: EIMS (70 electrovolt) m/z (relative intensity) 452 (1, M+). Oil (0.6 g, 1.3 mmol) is dissolved in a solution of methanol (30 ml) and water (15 ml) and add ammonium formate (1.7 g, 26 mmol) and palladium (0.3 g of 10% on charcoal). The mixture is refluxed for 45 minutes, palladium filters.

The solvent is evaporated in vacuum, the residue is distributed between ethyl acetate and 2M ammonium hydroxide solution. The organic phase is separated, dried (MgSO4), filtered and evaporated in vacuum, receiving 300 mg (yield 95%) named in the connection header.

Example 38

(R)-N-[5-methoxy-8-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

Named the title compound is obtained from (R)-2-amino-5-methoxy-8-(1-methylpiperidin-4-yl)-1,2, 3,4 - tetrahydronaphthalene, following the General process for the preparation of example 16. Purification on a column of silica gel,ml 53%) of crystals: etc. 237-242oC (decomposition); []21D-2(C=0,5, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 463 (15, M+).

Example 39

Chromatographic obtaining enantiomers of N-(4-morpholinyl)-8-(4-methylpiperazine)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide

N-(4-morpholinyl)-8-(4-methylpiperazine)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide (5 mg) dissolved in 4 ml of eluent consisting of acetonitrile and phosphate buffer pH 3.0, =0,1 (62,5:37,5 volume/volume). This solution is purified on a column of Nucleosil 7 C18(25250 mm) with the above mobile phase to remove the last eluruumiks contamination. The collected fractions of the main component concentrated under reduced pressure at 35-39oC. the Residue is dissolved in 30 ml of eluent consisting of 10 mm ammonium acetate, diethylamine and acetic acid (4000+2+2, vol/vol/vol, pH 5,26), and chiral prepreparation obtaining enantiomers of N-(4-morpholinyl)-8-(4-methylpiperazine)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide allocate prepreparation column (Chiral AGP (10150 mm), using predalone filled with the same stationary phase. Use the flow velocity of 2.0 ml/min and data registryroot pressure when 35-39oC. the pH of the concentrated fractions was adjusted to 10-11 using 5M NaOH and extracted with chloroform. The two organic phases are washed with water and dried with anhydrous magnesium sulfate. After filtration through glass wool organic filtrates evaporated in vacuum, obtaining the two enantiomers in the form of two yellow solids.

Example 40

(R)-2-N, N-dibenzylamino-5-(1-hydroxyethyl)-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-5-bromo-2-N, N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (1.4 g, 2.8 mmol) dissolved in freshly tetrahydrofuran (100 ml), washed with a current of argon and cooled to -78oC. To the solution was added tert-utility (2,6 ml, 1.4 M in pentane, 3.7 mmol) and reddish solution was stirred at ambient temperature for 10 minutes. Add acetaldehyde (320 μl, 5.7 mmol) and the reaction mixture stirred at -78oC for 10 minutes, at 0oC for 2 hours and at room temperature for 10 minutes. The reaction is quenched with water and the solvent is evaporated in vacuum. The residue is partitioned between diethyl ether (100 ml) and 2M NH3(20 ml) and the aqueous phase extracted with diethyl ether (20 ml). The combined organic layers washed with saturated saleonce silica gel, using as eluent chloroform/methanol/conc. NH3(95:5:0.5), and give 910 mg (yield 68%) named the title compound as a yellowish foam; ESI m/z (relative intensity) 470 (100, M+1).

Example 41

(R)-2-amino-5-ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-5-(1-gadoxetic)-1,2,3,4-tetrahydronaphthalen (1.6 g, 3.4 mmol) dissolved in acetic acid (80 ml) and stirred at 100oC for 2 hours. The solvent is evaporated in vacuum and the residue is dissolved in methanol (150 ml). Add palladium (10%) on charcoal (600 mg) and the solution washed with a stream of nitrogen. To the solution was added ammonium formate (1.7 g, 28 mmol) and the reaction mixture stirred at 65oC for 2 hours. The catalyst is filtered off, the solvent is evaporated in vacuum, obtaining 1.3 g of crude product. The residue is distributed between methylene chloride (120 ml) and 2M NH3(30 ml). The organic phase is washed with saturated saline (20 ml) and dried (MgSO4). The solvent is evaporated in vacuum, obtaining 740 mg (yield 79%) named the title compound as a white semi-crystalline solid: EIMS (70 electrovolt) m/z (relative intensity) 273 (24, M+).

Example 43

(R)-N-[5-ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinoethyl)benzamide

4-morpholinobenzenediazonium acid (180 mg, 0.77 mmol; described in: J. Med. Chem. 1994, 37(26), 4538-4554) and 1,1'- carbonyldiimidazole (130 mg, 0.80 mmol) dissolved in dry N,N-dimethylformamide and stirred at 75oC for 2 hours. After cooling to room temperature the m N,N-dimethylformamide, the reaction mixture is stirred for 60 hours. The solvent is evaporated in vacuum and the residue is distributed between methylene chloride (60 ml) and 2M NH3(5 ml). The organic phase is washed with saturated saline (10 ml) and dried (Na2SO4). Evaporation of the solvent in vacuo gives 360 mg of crude product. Purification using column chromatography on silica gel using as eluent chloroform/methanol/conc. NH3(95:5:0.5 to) give 240 mg (yield 65%) named in the title compounds as white solids: I. ii. 213-214oWith; EIMS (70 electrovolt) m/z (relative intensity) 490 (27, M+); []21D-28(C=0,15, chloroform).

Example 44

(R)-2-N, N-dibenzylamino-5-deformedarse-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

To a solution of (R)-2-N,N-dibenzylamino-5-hydroxy-8-(4-methyl-piperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (1 g, 2.3 mmol) in 2-propanol (75 ml) is added sodium hydroxide (2.8 g, 69 mmol) with stirring until most part will not dissolve (1.5 hours), the reaction mixture is heated to 65oC. Chlorodifluoromethane are passed through the reaction solution with vigorous stirring for 6 minutes, the reaction mixture is allowed to cool to room Trofim ether and water. The phases are separated, the organic phase is dried (Na2SO4), filtered and evaporated in vacuum. Purification on a column of silica gel using as eluent chloroform/ethanol saturated NH3(100: 1) to give 230 mg (yield 21%) of a thick colorless oil: []21D+119(c= 0.5, chloroform). EIMS (70 electrovolt) m/z (relative intensity) 491 (1, M+);

Example 45

(R)-2-amino-5-deformedarse-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

Named the title compound is obtained from (R)-2-N,N-dibenzylamino-5-deformedarse-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene, following the General process for the preparation of example 10. Yield 67 mg (42%) of a thick colorless oil: EIMS (70 electrovolt) m/z (relative intensity) 311 (28, M+).

Example 46

(R)-N-[5-deformedarse-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

Named the title compound is obtained from (R)-2-amino-5-deformedarse-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene, following the General process for the preparation of example 25. Purification on a column of silica gel using as eluent chloroform/ethanol with NH3(100:3) to give 26 mg (yield 24%) of white crystals: I. ii. 222-223oC; []2UP>);

Example 47

(R)-2-N-[8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-cryptomelane

It chilled with ice to a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.44 mmol) and triethylamine (91 μl, 0.66 mmol) in methylene chloride (20 ml) is added dropwise 4-(trifluoromethyl)benzoyl chloride (96 mg, 0.46 mmol) in methylene chloride (5 ml). After adding the reaction solution was allowed to mix at ambient temperature for 15 minutes and then washed with diluted aqueous sodium hydrogen carbonate solution. The phases are separated, the organic phase is dried (Na2SO4), filtered and evaporated in vacuum to give crude product which is purified on a column of silica gel using as eluent chloroform/ethanol saturated N (100:2). Yield: 150 mg (81%) named the title compound as white crystals: I. p. 203-204oC; []21D-20(c=1.0 in chloroform); EIMS (70 electrovolt) m/z (relative intensity) 417 (10, M+);

Example 48

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-cryptomelane

(R)-N-[8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-cryptomelane (80 mg, 0,19 mmol) and sodium acetate (200 mg) RA who have dropwise bromine (34 mg, 0.21 mmol), the mixture was stirred at ambient temperature for 2 hours. Add 2M sodium hydroxide solution (100 ml), the mixture is extracted with diethyl ether (250 ml). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification on a column of silica gel using as elution solvent of methylene chloride/ethanol saturated NH3(94: 6) to give 80 mg (yield 85%) named in the title compounds as white solids: I. ii. 229-230oC; []21D-5,4(C=1.0 in chloroform); EIMS (70 electrovolt) m/z (relative intensity) 495 and 497 (3, M+);

Example 49

(R)-2-N, N-dibenzylamino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-5-bromo-2-N, N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (400 mg, 0.79, which mmol) dissolved in freshly tetrahydrofuran (40 ml), washed with a stream of argon and cooled to -78oC. To the solution was added tert-utility (740 μl, 1.4 M in pentane, 1.0 mmol). The reddish solution was stirred at ambient temperature for 10 minutes. Add bromatology ether (65 μl, of 0.79 mmol), the reaction mixture was stirred at -78oC for 1 hour, when arevut. The residue is partitioned between diethyl ether (70 ml) and 2M NH3(15 ml), the aqueous layer was extracted with diethyl ether (20 ml). The combined organic layers washed with brine (15 ml) and dried (MgSO4). The solvent is evaporated, receiving 330 mg of crude product. Purification on a column of silica gel using as eluent chloroform/methanol/conc. NH3(250: 5: 0.5) and (180:5:0.5) with the network 160 mg (yield 43%) named the title compound as a yellowish oil: EIMS (70 electrovolt) m/z (relative intensity) 469 (4, M+); []21D+33(C=0.13 chloroform);

Example 50

(R)-2-amino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (160 mg, 0.34 mmol) is dissolved in methanol and the solution is washed with a stream of nitrogen. Add palladium (10%) on charcoal (80 mg) and formate ammonia (170 mg, 2.7 mmol). The reaction solution was stirred at 65oC for 2 hours. The catalyst is filtered off, the solvent is evaporated in vacuum, receiving 97 mg of crude product. Purification using preparative TLC using as eluent chloroform/ethanol saturated with ammonia (8: 1), Mae is sustained fashion intensity) 289 (40, M+); []21D-10(C=0.06 chloroform);

Example 51

(R)-N-[5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

4-morpholinomethyl acid (54 mg, 0.26 mmol) dissolved in dry N, N-dimethylformamide (1 ml) and added 1,1'-carbonyldiimidazole. The reaction mixture was stirred at 75oC for 1.5 hours and cooled to room temperature. Add a solution of (R)-2-amino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (72 mg, 0.25 mmol) in dry N,N-dimethylformamide (3 ml). The reaction mixture was stirred at room temperature for 15 hours. The solvent is evaporated, receiving 160 mg of crude product. Purification using preparative TLC using as an eluent of chloroform/ethanol/conc. NH3(95:5:0.5 to) give 95 mg (yield 80%) named in the title compound in the form of solids: I. ii. 200oWith (Razlog); (EIMS (70 electrovolt) m/z (relative intensity) 478 (7, M+); []21D-46(C=0.12 chloroform);

Example 52

(R)-2-N, N-dibenzylamino-5-hydroxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-5-bromo-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1, 2,3,4-tetrahydronaphthalen (800 mg, 1.6 to the P>C. To the solution was added tert

utility (1.5 ml, 1.4 M in pentane, 2.1 mmol), the reaction mixture was stirred at room temperature for 10 minutes. Add methylchloroform (250 μl, 3.2 mmol), the reaction mixture was stirred at -78oC for 50 minutes and at 0oC for 1 hour. The reaction is quenched with water, the solvent is evaporated in vacuum. The residue is partitioned between diethyl ether (90 ml) and 2 M NH3(15 ml). The organic layer was washed with saturated saline (10 ml) and dried (MgSO4). The solvent is evaporated in vacuum, obtaining 770 mg of crude product. Purification using column chromatography on silica gel using as eluent chloroform/ethanol/conc. NH3(250: 5: 0.5 to) give 610 mg of (R)-5-carboxymethyl-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (containing 13% of the corresponding 5-hydrogen equivalent) in the form of a yellowish oil: EIMS (70 electrovolt) m/z (relative intensity) 483 (1, M+). Methyl ester (610 mg, 1.1 mmol) dissolved in freshly tetrahydrofuran (35 ml), add alumoweld lithium (120 mg, 3.1 mmol). The reaction mixture was stirred at 45oC for 2 hours followed by cooling to room temperature the Oh temperature for 2.5 hours. The precipitate is filtered off, the solvent is evaporated in vacuum, obtaining 730 mg of crude product. Purification using column chromatography on silica gel using as eluent chloroform/methanol/conc. NH3(95; 5:0,5) give 360 mg (yield 50%) named the title compound as a white foam: EIMS (70 electrovolt) m/z (relative intensity) 455 (1, M+); []21D+44(C=0,12, chloroform).

Example 53

(R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-5-hydroxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (360 mg, 0.78 mmol) dissolved in methanol (35 ml), added palladium (10%) on activated carbon (170 mg) and the solution washed with a stream of nitrogen. To the solution was added ammonium formate (390 mg, 6.2 mmol), the reaction mixture is stirred at 65oWith over 13 hours. The catalyst is filtered off, the solvent evaporated in vacuum, getting 220 mg of residue. Raw hydroxymethylene compound is dissolved in acetic acid (25 ml), added palladium (10%) on charcoal (60 mg), the solution washed with a stream of hydrogen. The reaction mixture hydrogenizing at room temperature and at atmospheric pressure for 4 chaseway by hydrogenation at room temperature and under atmospheric pressure for 24 hours. The catalyst is filtered off and the solvent is evaporated in vacuum. The residue is partitioned between diethyl ether (70 ml) and conc. NH3and the organic phase is washed with saturated saline (5 ml). The organic layer is dried (gS4) and the solvent is evaporated in vacuum, receiving 120 mg (yield 61%) named in the title compound in the form of a semi-crystalline white solids: EIMS (70 electrovolt) m/z (relative intensity) 259 (20, M+); []21D-1(C=0,09, chloroform).

Example 54

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

4-morpholinomethyl acid (92 mg, 0.44 mmol) dissolved in dry N, N-dimethylformamide (2 ml) and washed with a stream of nitrogen. To the solution was added 1,1'-carbonyldiimidazole (76 mg, 0.47 mmol) and the reaction mixture is stirred at 75oC for 1.5 hours. The solution is cooled to room temperature, add (R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2, 3,4-tetrahydronaphthalen (110 mg, 0.42 mmol), dissolved in dry N,N-dimethylformamide (2 ml). The solution was stirred at room temperature for 30 hours. The solvent is evaporated in a vacuum, getting 290 mg of crude product. Cleaning with prepare mg (yield 73%) named in the title compounds as white solids: etc. >231oWith (Razlog. ); EIMS (70 electrovolt) m/z (relative intensity) 448 (3, M+); []21D-60(C=0,15, chloroform).

Example 55

(S)-2-amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalen

Named the title compound is synthesized in accordance with the method of example 21, using (S)-form; EIMS (70 electrovolt) m/z (relative intensity) 257 (17, M+,81VG), 255 (20: M+,79Br).

Example 56

(S)-8-bromo-2-N,N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalen

Named the title compound is synthesized in accordance with the method of example 22, using (S)-form; EIMS (70 electrovolt) m/z (relative intensity) 437 (38, M+,81VG), 435 (20: M+,79Br).

Example 57

(S)-2-N, N-dibenzylamino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

Named the title compound is synthesized in accordance with the method of example 23 using (S)-form; EIMS (70 electrovolt) m/z (relative intensity) 455 (10, M+).

Example 58

(S)-2-amino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

Named the title compound is synthesized in accordance with the method of the PR is example 59

(S)-N-[5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

Named the title compound is synthesized in accordance with the method of example 25 using (S)-form: etc., 229-232oC; []21D+48(C=1.0, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 465 (92, M+).

Example 60

(R)-N-[5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

Named the title compound is synthesized in accordance with the method of example 25, using the product from example 10: etc., 84-88oC; []21D-46(C= 1.0, chloroform); EIMS (70 electrovolt) m/z (relative intensity) 450 (32, M+).

Example 61

(R)-2-N, N-dibenzylamino-8-(4-benzylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalen

A solution of (R)-2-N, N-dibenzylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (58 g, 0.14 mol), N-benzylpiperazine (31 g, 0.18 mol), R-BINAP (6.7 g, 11 mmol), Tris(dibenzylideneacetone) dipalladium(0) (4.4 g, 4.8 mmol) and tert-piperonyl sodium (19 g, 0.2 mol) are heated in argon at 100oC for 17 hours. The mixture is cooled to ambient temperature and filtered through a layer of celite. The solvent is removed and the crude residue purified by column connection in the form of a light brown oil. []D20= +63(C= 1, SNS3); EIMS (70 electrovolt) m/z (relative intensity) 501 (1, M+).

Example 62

(R)-2-N, N-dibenzylamino-5-bromo-8-(4-benzylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalen

To a solution of (R)-2-N,N-dibenzylamino-8-(4-benzylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (61 g, 0.12 mol) and sodium acetate (148 g, 1.8 mol) in acetic acid (2 l) was added with stirring bromide (24 g, 0.15 mol). The mixture is stirred for 5 minutes at room temperature, the solution is evaporated in vacuum. The residue is partitioned between diethyl ether (1.5 l) and water (1 l). The organic phase is collected and extracted with aqueous sodium hydroxide solution (5 ml), washed with brine, dried (NaSO4), filtered and evaporated in vacuum, obtaining 70 g of brown oil. The oil is purified on a column of silica gel, using as eluent heptane/ethyl acetate (5:1) to give 41 g (yield 58%) named in the title compound in the form of oil. []D20= +19(c= 1, SNS3); EIMS (70 electrovolt) m/z (relative intensity) 579 and 581 (0,2, M+).

Example 63

(R)-2-N, N-dibenzylamino-5-methyl-8-(4-benzylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalen

A solution of (R)-2-N, N-dibenzylamino-5-bromo-which argon is cooled to -70oC, followed by adding dropwise n-utility (36 ml, 89 mmol; 2.5 M in hexane) over 1 hour. The solution was stirred at -70oC for 2 hours and slowly add logmean (9.3 g, 65 mmol) dissolved in anhydrous tetrahydrofuran (25 ml). The solution was kept at -70oC for 1 hour and then at 0oWith another hour, and then quenched by adding 2-propanol (8 ml). The solvent is evaporated and the residue is distributed between methylene chloride (700 ml) and water (350 ml). The organic layer is collected and the aqueous phase is extracted with methylene chloride (200 ml). The combined organic phase is dried (Na2SO4), filtered and evaporated, receiving 31 g of brown oil. The oil is purified on a column of silica gel, using as eluent heptane/diethyl ether (5:1) to give 20 g (yield 64%) named in the title compound in the form of oil. EIMS (70 electrovolt) m/z (relative intensity) 515 (2,+).

Example 64

(R)-2-amino-5-methyl-8-(piperazine-1-yl)-1,2,3,4-tetrahydronaphthalen

A mixture of (R)-2-N, N-dibenzylamino-5-methyl-8-(4-benzylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (20 g, 38 mmol), ammonium formate (57 g, 0.98 mol) and 10% palladium on charcoal (5.6 g) is refluxed in methanol (2 l) in accordance with the mind, the residue is distributed between methylene chloride (750 ml) and aqueous solution of ammonia (2 M, 250 ml). The organic phase is collected, the aqueous phase is re-extracted with methylene chloride (250 ml). The combined organic phases are dried (Na2SO4), filtered and evaporated in vacuum, obtaining 8.8 g (yield 95%) named in the title compound in the form of oil. The oil is triturated with diethyl ether, receiving light brown crystals: I. ii. 204-205oWith; EIMS (70 electrovolt) m/z (relative intensity) 245 (31, M+).

Example 65

Tert-butyl(R)-4-(4-methyl-7-amino-5,6,7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylate

A solution of (R)-2-amino-5-methyl-8-(piperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (8,3 g, 34 mmol) and triethylamine (4.0 g, 40 mmol) in methylene chloride (2 l) cooled to 2oC and added dropwise di-tert-BUTYLCARBAMATE (7,4 g, 34 mmol) in methylene chloride (250 ml) for 30 minutes. The mixture is stirred at room temperature for 1 hour, followed by addition of an aqueous solution of sodium bicarbonate (500 ml). The phases are separated, the organic phase is dried (Na2SO4), filtered and evaporated in vacuum. The crude product is purified on a column of silica gel, using as eluent methylene chloride/methanol/NH3(waters.tyranny with diethyl ether. EIMS (70 electrovolt) m/z (relative intensity) 345 (37, M+).

Example 66

(R)-N-[5-methyl-8-(4-tert-butyloxycarbonyl-1-yl)-1, 2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

To a solution of 4-morpholinomethyl acid (2.5 g, 12 mmol; described in: Degutis, J. ; Rasteikiene, L.; Degutinene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) in anhydrous N,N-dimethylformamide (120 ml) is added 1,1'-carbonyldiimidazole (2.1 g, 13 mmol) parts in an argon atmosphere. The solution is heated to 75oC for 30 minutes and then cooled to room temperature. To the solution is added dropwise tert-butyl(R)-4-(4-methyl-7-amino-5,6,7,8-tetrahydro-1-naphthyl)piperazine-1-carboxylate (3.7 g, 11 mmol) in anhydrous N, N-dimethylformamide (60 ml) and the mixture is stirred for 24 hours. The solvent is evaporated in vacuo, the crude product is purified on a column of silica gel, using as eluent heptane/ethyl acetate (3:2), receiving of 4.2 g (yield 74%) named in the title compound in the form of butter.

13C-NMR (75 MHz, D13) 166; 155; 153; 135; 132; 130; 128; 128; 125; 117; 114; 79; 66; 52; 48; 45; 32; 28,5; 29,5; 26; 19.

Example 67

(R)-N-[5-methyl-8-(piperazine-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl

To a solution of (R)-N-[5-methyl-8-(4-tert-butyloxycarbonyl-piperazine-1-yl)-1,2,3,4-tetrahydro-2-the slot (12 ml). The solution was stirred at room temperature for 24 hours and the solvent evaporated in vacuum. The residue is distributed between methylene chloride (250 ml) and 5 M aqueous solution of sodium hydroxide (100 ml, pH 10-11). The organic phase is collected, the aqueous phase is re-extracted with methylene chloride (100 ml). The combined organic phase is dried (Na2SO4), filtered and evaporated in vacuum. The crude product is purified on a column of silica gel, using as eluent methylene chloride/methanol/ NH3(aq.) (10:0,8:0,08), obtaining 3.2 g (yield 92%) named in the title compound in the form of oil, which crystallized (light brown crystals), triturating in diethyl ether: etc., 207-210o[]D20= -57(C=0,5, SMS3); EIMS (70 electrovolt) m/z (relative intensity) 434 (23, M+).

Example 68

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-chlorobenzamide

To a solution of (R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (52 mg, 0.20 mmol) and triethylamine (1 ml, 7.7 mmol) in methylene chloride (10 ml) add a solution of 4-chlorobenzylchloride (50 mg, 0.29 mmol) in methylene chloride (10 ml) and the reaction mixture was stirred at 0oC for 30 minutes. Paramashiva is. the STATCOM purified on a column of silica gel, using as eluent ethyl acetate containing triethylamine (7.5 percent), receiving 50 mg (yield 63%) named the title compound as white crystals: I. ii. 210-212oWith; EIMS (70 electrovolt) m/z (relative intensity) 397 (28, M+).

Example 69

(R)-2-N,N-dibenzylamino-8-bromo-1,2,3,4-tetrahydronaphthalen

(R)-8-bromo-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (50 g, to 0.19 mol) is partitioned between diethyl ether (700 ml) and 2M aqueous NaOH solution (100 ml). The aqueous layer was extracted with diethyl ether (50 ml), the combined organic phase was washed with saturated brine (75 ml). The ether layer is dried (Na2SO4), the solvent evaporated in vacuum, obtaining a 43.3 g of free base. The base is stirred in acetonitrile (600 ml) and add benzylbromide (54 ml, 0.46 mol), potassium carbonate (66 g, 48 mol), potassium iodide (200 mg, 1 mmol) and 100 ml of acetonitrile, the reaction mixture is heated to boiling under reflux. After stirring for 9 hours inorganic salt is filtered, followed by evaporation of the solvent in vacuo, receiving 91 g of residue. The crude product is dissolved in diethyl ether (100 ml), cooled on ice, slowly doba is xanam (1 liter). Add diethyl ether (1.5 l) and 1 M aqueous NaOH solution (150 ml), the mixture is stirred for 2 hours. The phases are separated, the aqueous phase is re-extracted with diethyl ether (100 ml), the combined organic layers washed with saturated saline (100 ml). The organic phase is dried (Na2SO4) and the solvent evaporated in vacuum, receiving 73 g (yield 94%) named the title compound as a yellow oil. An analytical sample purified using preparative TLC on silica gel, using as eluent chloroform/hexane (1:5); []22D+134(C= 0,72, SMS3). EIMS (70 electrovolt) m/z (relative intensity) 405 and 407 (6 and 9 M+).

Example 70

(R)-2-N, N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (48 g, 118 mmol) and 4-methylpiperazine (16 ml, 0.14 mol) is dissolved in toluene (450 ml) and washed with a stream of argon. To the solution was added (R)-(+)-2,2'-bis(diphenyl)phosphino-1,1'-binaphthyl (5.5 g, 8.9 mmol), Tris(dibenzylideneacetone)dipalladium(0) (3.4 g, 3.7 mmol) and tert-piperonyl sodium (16 g, 0,17 mmol), the reaction mixture was stirred at 85oC for 3 hours. Filtration through Celite using chloroform/matureadult. Purification using column chromatography on silica gel, using as eluent ethyl acetate/triethylamine (100:1), gives 44 g (yield 88%) named the title compound as a yellowish oil which crystallizes after some time: so p. 82-84oWith; EIMS (70 electrovolt) m/z (relative intensity) 425 (26, M+) []22D+40(C=0,57, SMS3).

Example 71

(R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (47 g/ 0/11 mmol) dissolved in acetic acid (480 ml) and loaded into a glass Buchi autoclave (1 liter). To the solution was added 10% Pd/C (9.4 g, containing 50% water). The reaction mixture was stirred at 70oC and at a pressure of 5 bar of hydrogen for 10 hours. The catalyst was removed by filtration and the solvent evaporated in vacuum, receiving 65 g of raw material in the form of oil. The raw material used in the next step without isolation of the free amine. An analytical sample is obtained by distributing the crude product between methylene chloride and aqueous NH3. The phases are separated, the organic phase is washed with saturated salt solution, dried (Na2SO4) and purified using it is getting named the title compound as a brownish oil: EIMS (70 electrovolt) m/z (relative intensity) 245 (10, M+); []25D-2,7(C=1,0, SMS3).

Example 72

(R)-2-amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (27 g, 0.11 mmol) and sodium acetate (9.6 g, 0.12 mol) is dissolved in acetic acid (145 ml). To the solution was added bromine (6,0 ml, 0.12 mmol) dissolved in acetic acid (145 ml) for 13 minutes at a maximum temperature of the 23oC. After complete addition, the reaction mixture was stirred at room temperature for 1.25 hours. The solvent is evaporated in vacuum, the additional amount of acetic acid (60 ml) is added and evaporated. The residue is distributed between ethyl acetate (300 ml) and water (100 ml) and cooled on ice. the pH was adjusted to 11-12 by addition of aqueous NaOH (45%) and the phases are separated. The aqueous layer was extracted with ethyl acetate (2200), the combined organic phases are washed with saturated brine (80 ml) and dried (Na2S04). The solvent is evaporated in vacuum, obtaining 27 g named the title compound as a brownish oil: EIMS (70 electrovolt) m/z (relative intensity) 324 and 325 (22 and 17, M+); []22D+3,5(C=0,23, SMS3).

Example 73

o
C for 1.5 hours. The additional amount of benzaldehyde (21 ml, 208 mmol) and NN3(3.5 g, 52 mmol) is added in portions within 48 hours. The reaction mixture was stirred for another 7 hours, quenched with acetic acid (27 ml, 0.49 mol) and stirred at room temperature for 15 hours. To the solution was added aqueous NaOH (30 ml, 45%), after 3.5 hours, the solvent evaporated in vacuum. The residue is distributed between ethyl acetate (400 ml) and water (100 ml), pH adjusted to 11 aqueous NaOH (14 ml, 45%). The phases are separated, the aqueous phase is re-extracted with ethyl acetate (150 ml), the combined organic layer was washed with saturated saline (100 ml). The organic phase is dried (Na2SO4), the solvent evaporated in vacuum, receiving 68 g of crude product. Purification using column chromatography on silica gel using as eluent ethyl acetate/triethylamine (100:1 is high intensity) 504 and 505 (of 0.8 and 0.6, M+); []22D+25(C=1,09, CHCl3).

Example 74

(R)-2-N, N-dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-5-bromo-8-(4-methylpiperazin-1-or-1,2,3,4-tetrahydronaphthalen (16 g, 0.31 mol) is dissolved in freshly tetrahydrofuran (300 ml) and cooled to -78oC in argon atmosphere. To the solution was added n-utility (19 ml, 1.6 M in hexane, 0.31 mol) dropwise over 45 minutes at a maximum temperature of -76oC. the Dark green solution is stirred for another 20 minutes. Within 25 minutes added dropwise a solution of methyliodide (1.9 ml, 0.31 mol) in freshly tetrahydrofuran (10 ml) with a maximum temperature of -74oC, and disappears green staining. The reaction mixture was stirred at -78oC for 50 minutes and at 0oWith over 50 minutes the Reaction is quenched with isopropyl alcohol (3 ml) and the solvent evaporated in vacuum. The residue is distributed between ethyl acetate (300 ml) and water (30 ml), the phases are separated and the organic layer was washed with saturated saline solution (30 ml). After drying (Na2SO4) and evaporation of the solvent in vacuo receive 15 g of crude product. Purification using column chromatography on silicate compound as a brown oil: EIMS (70 electrovolt) m/z (relative intensity) 439 (5, M+); []22D+86(=0,05, SMS3)

Example 75

(R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N, N-dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (28 g, 64 mmol) is dissolved in acetic acid (280 ml) and loaded into a glass Buchi autoclave (1 liter). Add 10% palladium on charcoal (2.8 g, containing 50% water). The reaction mixture was stirred at 70oWhen pressure 5 bar of hydrogen for 3.5 hours. The catalyst is filtered off, the solvent evaporated in vacuum. The residue is distributed between ethyl acetate (400 ml) and water (100 ml) and cooled in an ice bath, the pH was adjusted to 12 by addition of aqueous NaOH (45%), the phases are separated. The aqueous phase is re-extracted with ethyl acetate (2100 ml) and the combined organic layer was washed with saturated saline (50 ml) and dried (PA2SO4). Evaporation of the solvent in vacuo gives 18 g (yield 99%) named the title compound as a brown oil: EIMS (70 electrovolt) m/z (relative intensity) 259 (34, M+); []22D-1,1(C=0,09, SMS3)

Example 76

Salt (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

oWith in a minute, starting from room temperature. The samples were tested in aluminum cells with leaky caps in a stream of nitrogen. Acid (2S,3S)-tartrate (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (150 mg, 0.33 mmol) dissolved in tetrahydrofuran (3 ml) by heating and added dropwise D-(-)-tartaric acid (110 mg, 0.69 mmol) dissolved in tetrahydrofuran (3 ml). A white precipitate filtered and washed with tetrahydrofuran, receiving 180 mg (yield 86%). The crude salt (170 mg) is recrystallized from 3% aqueous solution of acetone (30 ml), after settling for 3 hours at room temperature the flask was placed in a freezer for about 65 hours. The solid is filtered and washed with cold acetone, receiving 120 mg (yield 61%) of white crystals: I. ii. 142-148oC. Analyte. calculated for C27H36N4O2WITH4H6O62H2O: C, 58,7; H 7,0; N 8,8 Found: 58,6; N 7,1; N 8,8

Example 77

Acid (2R, 3R)-tartaric (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (150 M0,69 mmol), dissolved in tetrahydrofuran (3 ml). A white precipitate filtered and washed with tetrahydrofuran, receiving 180 mg (yield 86%). The crude salt (180 mg) is recrystallized from 3% aqueous solution of acetone (48 ml) (insoluble material is filtered) and after settling overnight at room temperature, the solid is filtered, receiving 8 mg (yield 61%). The solvent is removed from the mother liquor, gently flowing nitrogen to remove 4 ml Flask allowed to stand at room temperature for 65 hours and then placed in the freezer for 5 hours. The solid is filtered and washed with cold acetone, receiving 61 mg (yield 29%) of white crystals: I. ii. 120-130oC. Analyte. calculated for C27H36N4O2WITH4H6O62H2About: With, Of 58.7; H 7,0; N 8,8 Found: With The 58.9; H 7,1; N 8,6.

Example 78

Bansilalpet (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (2 ml) by heating and added dropwise to benzosulfimide acid (40 mg, 0.24 mmol) dissolved in tetrahydrofuran (4 ml). Add diethyl ether and is aloe solid, which store in a desiccator over blue gel: etc. >250oC. Analyte. calculated for C27H36N4O2WITH6H6O3S2About: With, And 63.4; H 6,8; N 9,0 Found: From 63.1; H 7,0; N 8,7

Example 79

Acid 1,2-etandisulfonat (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (3 ml) by heating and added dropwise dehydrate 1,2-ethicolegal acid (55 mg, 0.24 mmol) dissolved in tetrahydrofuran (2 ml). Add diethyl ether (2 ml) and the resulting solid is filtered and washed with tetrahydrofuran/diethyl ether, obtaining white solid, which was stored in a desiccator over blue gel: T. p. 220oC. Analyte. calculated for C27H36N4O2C2H6O64H2O: C, 48,9; N 7,1; N 7,9 Found: From 49.1; H 6,8; N 7,6

Example 80

Acid maleate (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (2 ml) and to the clear solution was added diethyl ether (5 ml), getting oil. The solvent is decanted and the resulting oil triturated with diethyl ether. The solid is filtered and washed with diethyl ether, obtaining white solid, which was stored in a desiccator over blue gel: T. p. 160oWith (Razlog). Analyte. calculated for C27H36N4O2C4H4O4H2O: C, 63, 8mm; N 6,9; N 9,6 Found: 63,7; N 7,2; N 9,3

Example 81

Acid sulfate (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (2 ml) by heating and added dropwise sulfuric acid (25 mg, 0.24 mmol) dissolved in tetrahydrofuran (1 ml). A white precipitate filtered and washed with tetrahydrofuran, receiving 110 mg (yield 89%). The crude salt is recrystallized from H2O (12 ml) and leave in the freezer overnight. The solid is filtered and washed with cold water, getting 28 mg (yield 31%) of white solids: I. ii. 230oWith (Razlog). Analyte. calculated for C27H36N4O2H2O4S2O: C, 57,4; N 7,1; N 9,9 Found: With 57.7; H 7,4; N 9,9

Example 82

Gluconate (R)-N is Jn-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in ethanol (3 ml) and added dropwise a 50% aqueous solution of D-gluconic acid (80 μl, 0.24 mmol). The solvent is removed in vacuum, obtaining a thick oil. The crude oil is recrystallized from 5% N2About in acetone solution (3 ml) and 10% H2O in acetone solution (3 ml), decanted and leave at room temperature for 65 hours. The solid is filtered and washed with cold 3% water in acetone solution, receiving 95 mg (yield 65%) of white solids: I. ii. 130-140oC. Analyte. calculated for C27H36N4O2C6H12O7H2O: C To 59.8; H 7,6; N 8,5 Found: 60,0; N 7,4; N 8,3

Example 83

Acid succinate (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (2 ml) by heating and added dropwise succinic acid (56 mg, 0.46 mmol) dissolved in tetrahydrofuran (2 ml). Add diethyl ether (4 ml) until the turbidity of the solution. The solution is heated to boiling under reflux and put aside to cool. The solid is filtered, receiving 42 mg (yield 34%) of white solids, cat (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (15 ml) and added dropwise methanesulfonyl acid (42 mg, 0.44 mmol) dissolved in tetrahydrofuran (5 ml). The solvent is removed in vacuum, obtaining white solid, which is recrystallized from acetone (5 ml) and then 15% N2About in acetone solution (7 ml). The crystals are filtered, receiving 37 mg (yield 31%) of light yellow crystals, which are stored in a desiccator over blue gel: similar 250oC. Analyte. calculated for C27H36N4O2CH4O3S22About: From, To 57.9; H 7,6; N 9,7 Found: 58,1; N 7,4; N 9,6

Example 85

Acid (S)-malate (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (20 ml) and added dropwise L-(-)-malic acid (59 mg, 0.44 mmol) dissolved in tetrahydrofuran (3 ml). The precipitate is filtered and the solid is recrystallized from 15% N2About in acetone solution (7 ml). The crystals are filtered, receiving 100 mg (yield 77%) of white crystals: I. ii. 200oC. Analyte. calculated for C
Likely citrate (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in tetrahydrofuran (15 ml) and added dropwise citric acid (51 mg, 0.27 mmol), dissolved in 10% H20 in tetrahydrofuran (5 ml). The solid material is filtered and recrystallized from 20% N2About in ethanol (5 ml). The solid is filtered, receiving 88 mg (yield 62%) of white crystals: I. ii. 160oC (decomp.). Analyte. calculated for C27H36N4O2C6H8O72H2O: C, 57, 9; N. Of 7.6; N 9,7 Found: 58,1; N 7,4; N 9,6

Example 87

Hydrochloride (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl (100 mg, 0.22 mmol) dissolved in anhydrous tetrahydrofuran (15 ml) and added dropwise Hcl in anhydrous diethyl ether (4M) until the solution becomes acidic. White precipitate was filtered and washed with diethyl ether, getting named the title compound as white crystals.

Pharmacology

Stimulation electric field release of [3is the electric field from a slice in the occipital region of the cortex of Guinea pigs, which plaincourault with [3H] 5-HT. The nature of the release is similar to the release caused by nerve stimulation, i.e. absoltutely release from serotonergically nerve endings, showing the dependence on the presence of CA2+in the incubation media. The release of [3H]-5-HT is regulated at the level of the nerve endings of autoreceptors in Guinea pigs (and humans), depending on the subtype h5-HT1Bthe receptor. Thus, agonist h5-HT1Breceptors reduces the amount of released [3H] 5-HT stimulation region, whereas the release increases antagonists of this receptor. Testing connections in this way is a convenient screening method to determine the strength and functional effect of new agonists and antagonists h5-HT1Breceptors.

Methods and materials

The composition of the buffer (mm): Panso3(25), NaH2PO4.H2O (1,2), NaCl (117), KS1 (6), MgS47H2O (1.2), CaCl2(1,3), EDTA Na2(0,03). The buffer is saturated with gas for at least 30 minutes before using. the pH of the buffer is about 7.2 at room temperature, but increases to 7.4 at 37oC.

Obtaining slices occipital h is tylonol part of the crust and make the cuts with a tool for making sections McIlwain. The white part of the fabric should first carefully removed with tweezers. Slices incubated in 5 ml of buffer in the presence of 5 mm parkeringsomrede. After incubation with 0.1 mm [3H] 5-HT for 30 minutes, the slices are transferred into a test tube for testing and thrice washed with the same buffer solution. Cuts plastic transfer pipette in camera superfusion and washed for 40 minutes buffer in the presence of absorption inhibitor citalopram 2.5 μm with a flow rate of 0.5 ml/min

Electrical stimulation of the release of [3H]-5-HT

Buffer, subjected superfusion, collected in 2 ml fractions. Cuts stimulate electricity pulses with a frequency of 3 Hz, a duration of 2 MS and a power of 30 mA for 30 minutes at 4 and 13 fractions. The test drugs were added, starting with 8 fractions to the end of the experiment.

Results

The first electric (or+) stimulation resulted in the release of a standard quantity of [3H] 5-HT. Before the first and second stimulation on Wednesday added antagonist h5-HT1Bthat led to dozozawisimam increase the release (S2after the second stimulation (see Fig.1).

The ratio of S2/S1that is about when the first stimulation (S1), is used to evaluate the effect of drugs on the release of transmitter.

The results are presented in tables 1 and 2.

1. Derivatives of 1,2,3,4-tetrahydronaphthalene formula I

< / BR>
where X represents N or CH;

Y represents NR2CH2, NR2-CO or CO-NR2,

where R2represents N or C1-C6-alkyl;

R1represents N or C1-C6-alkyl;

R3represents phenyl which may be mono - or Disaese R4,

where R4represents H, halogen, CN, CF3C1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms, selected from N and O, or COR8,

where R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O;

R9represents a C1-C6-alkyl, OCHF2, halogen, HE, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, in the form of (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or MES.

2. The connection is is a n

4. Connection on p. 1, where R3represents phenyl.

5. Connection on p. 1, where R3represents phenyl, which is substituted by an R4, optionally substituted heterocyclic ring containing one or two heteroatoms, selected from N and O, or COR8.

6. Connection on p. 1, where R8represents a heterocyclic ring containing two heteroatoms, selected from N and O.

7. Connection on p. 1, where R9represents a C1-C6-alkyl, OCHF2, halogen or C1-C6-alkoxy.

8. Connection on p. 1, where X represents N, Y represents NR2CO, and R9represents a C1-C6-alkoxy.

9. Connection on p. 1, where X represents N, Y represents NR2CO., R4represents morpholino or COR8and R9represents a C1-C6-alkoxy.

10. Connection on p. 1, where X represents N, Y represents NR2CO, and R9represents a C1-C6-alkyl.

11. Connection on p. 1, where X represents N, Y represents NR2CO., R1represents H, R3represents feeboy N, Y represents NR2CO., R4represents morpholino or COR8and R9represents a C1-C6-alkyl.

13. The connection that represents the

(R)-N-[5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-cryptomelane;

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-bromo-8-(piperazine-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzene;

(R)-N-[5-methoxy-6-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinosydnonimine;

(R)-N-[5-methyl-8-(piperazine-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl;

(R)-N-[5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinosydnonimine;

N-(4-morpholinyl)-8-(4-methylpiperazine)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide;

N-(morpholinoethyl)-8-(4-methylpiperazin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxamide;

(R)-N-[5-ethyl-8-(4-meteorito-2-naphthyl] -(4-morpholinoethyl)benzamide;

(R)-N-[5-deformedarse-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl; or (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl,

in free base form or pharmaceutically acceptable salt or MES.

14. The connection, which is (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinomethyl in free base form or pharmaceutically acceptable salt or MES.

15. Pharmaceutical composition having antagonistic in relation to the receptor 5-HT1Bactivity containing the active agent, optionally in combination with diluents, excipients or inert carriers, characterized in that as the active agent contains a therapeutically effective amount of a compound according to any one of paragraphs. 1-14 in the form of an enantiomer or racemate in the form of a free base or its pharmaceutically acceptable salt or MES.

16. The pharmaceutical composition according to p. 15 for the treatment of diseases mediated 5-hydroxytryptamine.

17. The pharmaceutical composition according to any one of p. 15 or 16 for the treatment of mood disorders, anxiety, personality notreble tobacco, autism, lack of attention, hyperactivity condition, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, disorders of thermoregulation, pain, hypertension, urinary incontinence, vasospasm and to control tumor growth.

18. The compound according to any one of paragraphs. 1-14 for the treatment of diseases, which shows the inhibition of the receptor 5-HT1B.

19. Connection on p. 18, for use in the treatment of diseases of the Central nervous system.

20. Connection on p. 19 for the treatment of mood disorders, anxiety, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disorders, alcoholism, tobacco abuse, autism, lack of attention, hyperactivity condition, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, disorders of thermoregulation, pain, hypertension.

21. Connection on p. 18 for the treatment of urinary incontinence, vasospasm and to control tumor growth.

22. The connection, as defined in paragraph 18, for the treatment of diseases mediated 5-hydroxytryptamine.

1Bincluding the introduction of a mammal, including man, in need of such treatment, a therapeutically effective amount of a compound defined in any of paragraphs. 1-14.

25. The method according to p. 24, where the specified condition chosen from the disorders of the Central nervous system and/or urinary incontinence, vasospasm and control of tumor growth.

26. The method according to p. 24 for the treatment of mood disorders, anxiety, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disorders, alcoholism, tobacco abuse, autism, disorders of attention, hyperactive state, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, disorders of thermoregulation, pain, hypertension.

27. The method according to p. 24 for the treatment of diseases mediated 5-hydroxytryptamine.

28. The method of obtaining the compounds of formula I on p. 1, where Y represents NR2CO., R2represents H, and X, R3and R9are specified in paragraph 1 values, including

A(i) acylation of compounds of formula

< / BR>
where R1represents a C1-C6-alkyl, AE activating reagent, or

A(ii) acylation of compounds of formula IN

< / BR>
where Rwithrepresents a protective group,

the activated carboxylic acid R3-L, where L is the deleted group, or carboxylic acid R3-COOH with an activating reagent, followed by removal of the protective group Rcexcept for the case when R9Deputy, which are sensitive to the specific atsiliruyuscimi agent.

29. The method of obtaining the compounds of formula I on p. 1, where Y represents NR2CO., R2represents H, and X, R3and R9are specified in paragraph 1 values, including the interaction of the compounds of formula WITH

< / BR>
with the compound of the formula Xl

< / BR>
where X represents the group that you want except for the case when R9is a Deputy, which is sensitive to a specific alkylating reagent.

30. The method of obtaining the compounds of formula I on p. 1 where Y represents NR2CO., R9represents halogen, and R1, R2and R3are specified in paragraph 1 values, including the interaction of the compounds of formula D

< / BR>
with a suitable halogenation agent such as VG2the hat is N or CH;

Z represents NH2or COOH;

R1represents N or C1-C6-alkyl;

R9represents a C1-C6-alkyl, OCHF2, halogen, HE, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl.

32. The compound of General formula

< / BR>
where Y represents CONR2,

where R2represents N or C1-C6-alkyl;

R3represents a C1-C6-alkyl, phenyl which may be mono - or Disaese R4,

where R4represents H, halogen, CN, CF3C1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms, selected from N and O, or COR8,

where R8represents a heterocyclic ring containing one or two heteroatoms, selected from N and O;

R9represents a C1-C6-alkyl, OCHF2, halogen, HE, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl.

 

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< / BR>
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