MXPA00002763A - Substituted chroman derivatives - Google Patents

Abstract

The present invention relates to new piperidinyl- or piperazinyl-substituted-3, 4-dihydro-2H-1-benzopyran derivatives having formula (I) wherein X is N or CH;Y is NR2CH2, CH2NR2, NR2CO, CONR2 or NR2SO2 wherein R2 is H or C1-C6 alkyl;R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl;R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted;n is 0-4;R9 is C1-C6 alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CONR6R7, CN, CF3, OH, C1-C6 alkoxy, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C1-C6 alkyl;or COR8;wherein R6, R7 and R8 are as defined above, as (R)-enantiomers, (S)-enantiomers or racemates in the form of a free base or pharmaceutically acceptable salts or solvates thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.

Description

DERIVATIVES SUBSTITUTED FROM CHROMINE Field of Invention.

The present invention relates to novel 3,4-dihydro-2H-l-benzopyran derivatives substituted with piperidinyl- or piperazinyl- as enantiomers- (R), (enantiomers) - (s) or racemates in free base form or salts pharmaceutically acceptable or solvates thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compound and the use of said compound in therapy.

An object of the invention is to provide compounds for therapeutic use, especially compounds that have ur. selective effect in a subgroup of 5-hydroxytryptamine receptors, designated as h5-HT? B receptors (previously called 5-HT? Dp receptors) in mammals including homore.

It is also an objective of the invention to provide compounds with a therapeutic effect after eral administration.

REF. 33004 Background of the Invention In several disorders of the central nervous system such as depression, anxiety, etc. They appear involved disturbances of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these psychological agonists. It seems that the increase of 5-HT neurotransmitters affects depressive mood and anxiety, while the increase of neurotransmitter noradrenaline affects the delay of symptoms that occur in patients with depression. The invention concerns compounds that have an effect on 5-HT neurotransmitters.

The activity of serotonin, or 5-HT, is thought to be involved in many different types of psychiatric disorders. Therefore it is believed that an increase in the activity of 5-HT is associated with anxiety, while a decrease in 5-HT has been associated with depression. Serotonin has been additionally implicated in such diverse conditions as eating disorders, gastrointestinal disorders, disorders of cardiovascular regulation and sexual disturbances.

The 5-HT receptors The various effects of 5-HT can be related to the fact that serotonergic neurons stimulate the secretion of several hormones, for example, cortisol, prolactin, β-endorphin, vasopressin and others. The secretion of each of these and other hormones appears to be regulated on a specific basis by several different subtypes of 5-HT (serotonin) receptors. To date, these receptors have been classified as 5-HT ?, 5-HT2, 5-HT3, 5-HT4, 5-HTs, 5-HT6, and 5-HT7, with " the 5-HT? receptor subsequently divided into the 5-HTiA, 5-HT? B, 5-HTID, 5-HT? E, and 5-HTIF subtypes Each receptor subtype is involved in a different function of serotonin and It has different properties.

Regulation of 5-HT transmission The release of 5-HT is feedback-regulated by two different subtypes of 5-HT receptors. The 5-HTXA inhibitory autoreceptors are located in the body of the cells in the raphé nucleus whose over stimulation by 5-HT decreases the impulse of propagation in the 5-HT neurons and therefore reduces the release of 5-HT to the nerve terminals. Another subtype of 5-HT inhibitory receptors is located on the 5-HT nerve terminals, the h5-HT? B receptors (the r5-HT1B receptors in rodents) that regulate the synaptic concentration of 5-HT by controlling the amount of -HT that is released. An antagonist of these autoreceptor terminals thereby increases the amount of 5-HT released by the nerve impulses that have been shown in in vitro and in vivo experiments.

The use of an antagonist of the terminal h5-HT? B autoreceptor could therefore increase the synaptic concentration of 5-HT and increase the transmission in the 5-HT system. This could thus produce an antidepressant effect making it useful as a medication for depression.

Other locations of the h5-HT1B receptor subtype also exist. A large part of these postsynaptic receptors appear to be located in the nerve terminals of other neuronal systems (also called heteroreceptors), as the h5-HT1B receptor mediates inhibitory responses. An antagonist of this receptor subtype could also increase the release of other neurotransmitters. of 5-HT.

The compounds that have activity by h5-HT? B can, according to well-known and recognized pharmacological tests, be divided into total agonists, partial agonists and antagonists.

Description of the invention The aim of the present invention is to provide compounds that have a selective effect on the h5-HT1B receptor, preferably antagonistic properties, as well as having a good bioavailability. The effect on the other receptors chosen from, for example, the 5-HT1A, 5-HT2A, Di, D2A, D3, oti and a2 receptors has been investigated.

Accordingly, the present invention provides compounds of general formula I ( where X is N or CH: Y is NR2CH2, CH2NR2, NR2CO, CONR2 or NR2S02 Wherein R2 is H or Ci-Ce alkyl; Ri is H, Ci-Cß alkyl or C3-C6 cycloalkyl R3 is C?-C6 alkyl, C3-C6 cycloalkyl or (CH2) n-aryl, where the aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, 0 and S and which may be mono or di-substituted with R4 and / or R5; wherein R4 is H, C? -C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C? -C6 alkoxide, NR6R7, 0CF3, S03CH3, S03CF3, S02NR6R7, phenyl, phenyl-Ci- Cß alkyl, phenoxide, Ci-Cβ alkylphenyl, an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O, S, SO and S02 where the substituent (s) is (are) selected from C6-C6 alkyl, C3-C6 cycloalkyl and phenyl-Ci-Ce alkyl; or COR8; wherein R 6 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R7 is H, alkyl C? -C6 or C3-C6 cycloalkyl; and s is C? -C6 alkyl, C3_C6 cycloalkyl CF3, NR6R7, phenyl, or a heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO, and S02; wherein R5 is H, OH, CF3, 0CF3, halogen, C? _C6 alkyl or C? -C6 alkoxide; n is 0-4; R9 is C? -C6 alkyl, C3-C6 cycloalkyl, 0CF3, 0CHF2 0CH2F, halogen, C0NR6R7, CN, CF3, OH, alkoxide C? _C6, NR6R7, S03CH3, S03CF3, S02NR6R7 / a heterocyclic or substituted or unsubstituted heteroaromatic ring containing one or two heteroatoms selected from N and 0, in wherein the substituent (s) is (are) alkyl C? _C6; or C0R8; wherein R6, R7 and s are as defined above, such as (R) -enantiomers, (S) -enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or a solvate thereof having a high selective effect in the h5-HT? B receptor and also shows sufficient bioavailability after oral administration.

In the present context the C CC6 alkyl may be linear or branched. The C CC6 alkyl can be methyl, ethyl, n-propyl, 1-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl , n-hexyl or i-hexyl.

In the present context the alkoxide C? ~ C6 can be linear or branched. The alkoxide C? -C6 can be methoxide, ethoxide, n-propoxide, i-propoxide, u-butoxide, i-butoxide, s-butoxide, t-butoxide, n-pentyloxide, i-pentyloxide, t-pentyloxide, neo- pentyloxide, n-hexyl oxide or i-hexyl oxide.

In the present context the C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclohexyl.

In the present context, the halogen can be fluoro, chloro bromo or iodo.

In the present context the heteroatom ring containing one or two heteroatoms selected from N, O or S is preferably a 5- or 6- membered heteroaromatic ring and may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyra Oleyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring can be any substituted or unsubstituted.

In the present context the heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO or S02 may optionally contain a carbonyl functional group and a 5-, 6- or 7-membered heterocyclic ring is preferable and it may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidino, 1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.

A preferred embodiment of the invention relates to compounds of formula I wherein Y is NHCO or CONH that is amides. Of these compounds, the compounds wherein R 9 is C 1 -C 6 alkyl, C 1 -C 6 alkoxide, 0CHF 2 or 0CH 2 F and R 3 is unsubstituted phenyl, or mono- or di-substituted phenyl, and especially phenyl ortho-meta- or para- substituted, and particularly those wherein the R4 substituent is phenyl, phenyl-Ci-Ce alkyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF3, 4-piperidon-l-yl, n-butoxide or C0R8 wherein R8 is phenyl , cyclohexyl, 4-piperidon-1-yl, 1-piperazinyl, morpholino, CF 3, piperidino or NR 6 R are preferred.

Examples of combinations of substituents are: X is N, Y is CONR2, Rx is CH3, C2H5 or C3H-7, R2 is H, R3 is CH2-phenyl, R9 is CH3, C3H5 or C3H7; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is 0CH3; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H-7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, Rg is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3; X is CH, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is 0CH3; X is N, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is C0NR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is 0CH3; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is 0CH3; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is CH3, C2H5 or C3H7; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is 0CH3; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is 0CH3; X is N, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is C0R8, R8 is cyclohexyl, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is 0CH3; X is N, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C0, R2 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is 0CH3; X is N, Y is C0NR2, R: is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is 0CH3; X is CH, Y is NR2C0, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is 0CH3; X is N, Y is C0NR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is 0CH3; X is N, Y is NR2C0, RX is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3; X is N, Y is C0NR2, Rx is H, CH3f C2H5 or C3H7, R2 is H, R3 is (CH2) 2-f enyl, R9 is OCH3; X is N, Y is CONR2, Rx is H, CH3, C2HS or C3H7, R2 is H, R3 is phenyl, R is morpholino, R5 is H, Rg is OCH3; X is N, Y is CONR2, Rj. is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3; X is N, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is OCH3; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, Rg is OCH3; X is N, Y is NR2C0, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is OCH3; X is N, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is' OCH3; X is N, Y is C0NR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5, or C3H; X is CH, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5, C3H7; X is N, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H ,. R3 is CH2-phenyl, R9 is OCH3; X is N, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is OCH3; X is N, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R9 is CH3, C2H5, C3H7; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, Rg is 0CH3; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3; X is N, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino, R9 is OCH3; X is CH, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3; X is N, Y is- CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is morpholino, R5 is H, R9 is OCH3; X is CH, Y is CONR2, R, is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl R5 is H, R9 is OCH3; X is N, Y is NR2CO ,. Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino, Rg is OCH3; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is OCH3; X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, Rg is OCH3; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, Rg is CH3, C2H5 or C3H7; X is CH, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is 0CH3; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3; X is CH, Y is NR2C0, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is 0CH3; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R9 is 0CH3; X is N, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is C0R8, R8 is cyclohexyl, R9 is 0CH3; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is OCH3; X is CH, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is COR8, R8 is NR6R7, R6R7CH3, C2H5 or C3H7, R9 is OCH3; X is N, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-f enyl, R9 is OCH3. X is CH, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R9 is CH3, C2H5 or C3H7; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, Rg is OCH3; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R9 is OCH3; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, Rg is CH3, C2H5 or C3H7; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, Rg is CH3, C2H5 or C3H7; X is CH, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or- C3H7, R2 is H, R3 is (CH2) 2-f enyl, R9 is OCH3; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is 0CH3; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C H5 or C3H7; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is COR8, R8 is NR6R7, NR6R7CH3, C2H5 or C3H7, Rg is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Rj. is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, Rs is H, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2CO, R? is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, Rg is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is OCH3; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is CH3, C2H5 or C3H7; X is N, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is OCH3; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, Rg is 0CH3; X is N, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R9 is CH3, C2H5 or C3H7; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is CH3, C2H5 or C3H7; X is CH, Y is NR2CO, Rj. is H, CH3, C2H5 or C3H7, R2 is -H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-fyl, Rg is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is CONR2, RX is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is CH3, C2H5 or C3H7; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2Hs or C3H7; X is N, Y is CONR2, R? is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is 0CH3; X is N, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is C0R8, R8 is morpholino, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C0, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is N, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C0, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R is H, R9 is OCH3; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is CH3, C2H5 or C3H7; X is N, Y is NR2C0, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is C0R8, R8 is R5 is morpholino, Rg is CH3, C2H5 or C3H7; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C0, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R9 is CH3, C2H5 or C3H7; X is N, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2C07 Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R is morpholino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is CONR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is piperidino, R5 is H, R9 is 0CH3; X is N, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R is morpholino, R5 is H, R9 is OCH3; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H, Rg is CH3, C2H5 or C3H7; X is N, Y is CONR2, R? is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H, R9 is CH3, C2H5 or C3H7; X is CH, Y is C0NR2, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2) 2-phenyl, R9 is CH3, C2H5 or C3H7; X is CH, Y is NR2CO, Rx is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or 'phenylethyl, Rs is H, Rg is CH3, C2H5 or C3H7.

The preferred compounds are: (S) -N- [8-Methyl-5- (4-methyl-piperazin-1-yl) -3, 4-dihydro-2H-1-bezopyran-3-yl] -4- (dimethylaminocarbonyl) -enzyamide and N- ( 4-Morpholinophenyl) -8-methoxy-5- (4-methyl-piperazin-1-yl) -3, -dihydro-2H-l-benzopyran-3-carboxamide.

The compounds of the present invention are in the form of the racemate or the enantiomers (R) - or (S) - in the form of a free base or a pharmaceutically acceptable salt or solvate thereof. Compounds in the form of enantiomers (S) - are considered preferred.

Both the organic and inorganic acids can be employed to form salts with addition of pharmaceutically acceptable and non-toxic acids of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric acid, formic, hydrobromic, citric, acetic, lactic, tartaric, dibenzyltartaric, diacetyltartaric, palmoic, ethanedisulfonic, sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic, phenylacetic. , 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic, 3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, benzenesulfonic, p-toluenesulfonic , sulfanilic, naphthalenesulfonic, ascorbic, cyclohexyl sulfonic, fumaric, maleic and benzoic. These salts are readily prepared by methods known in the art.

Preferred solvates of the compounds of this invention are hydrates.

Pharmaceutical Formulations In a second aspect the present invention provides a pharmaceutical formulation that includes as an active ingredient a therapeutically effective amount of the compound of formula I as an enantiomer, a racemate in free base form or a pharmaceutically acceptable salt or solvate thereof, optionally in association with diluents , excipients or inert carriers.

According to the present invention the compounds of the invention could be normally administered, orally, rectally or by injection, in the form of pharmaceutical formulations that include the active ingredient in any free base or a pharmaceutically acceptable non-toxic acid addition salt per example, the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in the form of a pharmaceutically acceptable dose. The dosage forms can be solid, semi-solid or liquid preparations. Usually the active substance could constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for the projected preparations for injection and between 0.2 and 50% by weight for the preparations suitable for oral administration .

To produce pharmaceutical formulations containing the compound of the invention in the form of dosage units for oral application, the selected compounds can be mixed with a solid excipient for example, lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like and then tablets. If coated tablets are required, the cores prepared as described above, can be coated with a concentrated sugar solution which may contain for example gum arabic, gelatin, talcum, titanium dioxide, and the like, alternatively, the tablet may be coated with a polymer known to the person skilled in the art, dissolved in an easily volatile organic solvent or a mixture of organic solvents. The dyes can be added to these compounds to facilitate the distinction between tablets containing the active substances or different amounts of the active compound.

For the preparation of soft gelatine capsules, the active substance can be mixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatin capsules contain granules of the active substance using any of the excipients for the above-mentioned tablets, for example, lactose, sucrose, sorbitol, mannitol, starches (e.g., potato starch, corn starch or amylopectin), derivatives of cellulose or gelatin. Also the solids or semi-solids of the drug can be filled into hard gelatin capsules.

Dosing units for rectal applications can be solutions or suspensions or can be prepared in the form of suppositories that include the active substance in a mixture with a fatty base, or rectal gelatin capsules that include the active substance in a mixture with oil vegetable or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.1% to about 20% by weight of the active substance described herein, the balance being sugar and a mixture of ethanol, water, glycerol, and propylene glycol Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose as a thickening agent or other excipients known to the person skilled in the art.

Solutions for parenteral application by injection can be prepared in an aqueous solution of a pharmaceutically acceptable water soluble 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 and / or buffering agents and may conveniently be provided in various dosage units in ampoules.

Suitable daily doses of the compound of the invention in the therapeutic treatment of humans are around 0.01-100 mg / kg of body weight in peroral administration and 0.001-100 mg / kg of body weight in parenteral administration.

The compound of the invention can be used in combination with a 5-HT reuptake inhibitor, such as fluoxetine-, paroxenite, citalopram, clomipramine, sertraline, alaproclate or fluvoxamine, preferably paroxetine or citalopram. Another possible combination is to use the compound of the invention together with an oxidase-inhibiting monoamine, such as moclobemide, tranylcypramine, brofaromide or phenelzine, preferably moclobemide or phenelzine. Another possible combination is the compound of the invention together with a 5-HTIA antagonist, such as the compound described in WO96 / 33710, preferably (R) -5-carbamoyl-3- (N, -dicyclobutylamino) -8 -fluoro-3, 4-dihydro-2H-l-benzopyran.

Medical and Pharmaceutical Use In a further aspect the present invention provides the use of the compounds of formula I in therapies as an antagonist of h5-HT? B, partial antagonist or total antagonist, preferably as an antagonist and the use in the treatment of disorders mediated by -hydroxytryptamine. Examples of such disorders in the CNS such as mood disorders (depression, major depressive episodes, dysthymia, temporary affective disorders, depressive phases or bipolar disorders), anxiety disorders (obsessive-compulsive disorders, panic disorders with / without agoraphobia, phobia social, specific phobias, generalized anxiety disorders, posttraumatic stress disorders), personality disorders (impulse control disorders, tricotelomania), obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, deficits in attention, hyperactivity disorders, migraine, memory disorders (memory impairment associated with age, presenile and senile dementia), pathological aggression, schizophrenia, endocrine disorders (for example, hyperprolactinaemia), attacks, dyskinesia, disease of Parkinson's, thermoregulation, pain and hypertension. Other examples of disorders mediated by hydroxytryptamine are urinary incontinence, vasospasm, and controlled growth of tumors (eg, lung carcinoma).

Preparation Methods The present invention also relates to the processes for preparing the compounds of formula I. Through the following descriptions of such processes it is understood that, where appropriate, suitable protecting groups will be added, in a manner that is easily understood by one of the specialists in the technique of organic synthesis. Conventional methods for the use of such protecting groups as well as examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis" T.W. Greene, Wiley-Interscience, New York, 1991.

Methods of Preparation of intermediaries 1. In the case where Y is NR2CO and X is N (i) Benzylation of the compound of formula II, any racemate (described in: Thorberg, SO .; Hall, H .; Akesson, C; Svensson, K .; Nilsson, JLG Acta pharm., Sweden 1987, 24 (4) , 169-182) or as an enantiomer (described in: application of patent WO 93/07135), NH, OCH, (II) to obtain a compound of formula III by reaction with a suitable benzylating agent, for example, a benzyl halide, such as benzyl bromide, benzyl chloride or an activated alcohol, for example, benzyl mesylate or tosylate. The reaction can be carried out by using the salt or base of compound II in a suitable solvent, for example, N, N-dimethylformamide, acetone or acetonitrile, with a suitable base, for example NaOH, NaHCO 3, K 2 CO 3 or a trialkylamine, such as triethylamine at a reaction temperature within the range of +20 to +150 ° C. The presence of a suitable catalyst, for example, a metal, alkali metal iodide such as potassium iodide or sodium iodide, can increase the speed of the reaction. (ii) The demethylation of the compound of formula III (MY) to obtain a compound of formula IV can be carried out by treating the compound with an acid reagent such as HBr, Hl, HBr / CH3COOH, BBr3, ALC13, aqueous pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4SNa in a suitable solvent. Suitable solvents may be methylene chloride, or chloroform and at a reaction temperature between -78 ° C and +60 ° C. (iii) Conversion of the compound of formula IV to a compound of Formula V (IV) 00 it can be carried out by reaction with a compound of formula VI (SAW) wherein Lg denotes to leaving group, for example, a halogen such as chloride, bromide or iodide or an alkane- or an arenesulphonyloxy group such as a p-toluenesulphonyloxy group and Ra and Rb are hydrogen or a lower alkyl group, for example, methyl. The process can be carried out with a salt of the compound of formula IV obtained by reaction with a base such as K2C03, Na2C03, KOH, NaOH, BuLi or NaH. The reaction can be conducted in a suitable solvent, for example, an aprotic solvent such as dioxane, N, N-dimethylformamide, tetrahydrofuran, toluene, benzene, or petroleum ether, and the reaction can occur between + 20 ° C and +150 ° C. (iv) The rearrangement of a compound of formula V to a compound of formula VII (V) (Vil) it can be carried out in a suitable solvent, for example, an aprotic solvent such as N, N-dimethylformamide, dioxane, 1,2,3,3-tetramethylurea, tetrahydrofuran or hexamethylphosphoric t-riamide, with a suitable base, example, K2C03, KOH, potassium tert-butoxide or NaH, at a reaction temperature within the range of +20 ° C to +150 ° C.

The presence of a co-solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone or hexamethylphosphoric triamide in an appropriate concentration in the solvent can increase the speed of the reaction. (v) The hydrolysis of a compound of formula VII to a compound VII can be carried out under acidic conditions using acids such as H2SO4, HCl or HBr in a suitable solvent, for example, H20, ethanol, methanol or mixtures thereof, and the reaction can occur between +20 ° C and +100 ° C or under basic conditions using bases such as NaOH or KOH in a suitable solvent, for example, H20, ethanol, methanol or mixtures thereof, and at a temperature of reaction between +20 ° C and +100 ° C (vi) The conversion of a compound of formula VIII to a compound of formula IX (VIII) (W) it can be carried out by a) a reaction with a compound of formula X (X) wherein Ri is a C? -C6 alkyl or a C? -C6 cycloalkyl. The process can be carried out in a suitable solvent, for example an aprotic / anhydrous solvent such as tetrahydrofuran or N, -dimethylformamide, in the presence of a coupling reagent such as N, N-carbonyldiimidazole and the reaction can occur between +20 ° C and + 130 ° C. The reaction is followed by reduction of the imide with a suitable reducing agent, for example, LiAlH4, in a suitable solvent, for example diethyl ether or tetrahydrofuran, at a temperature between +20 ° C and reflux, or b) by reaction with a compound of formula XI Lg N-R, (XI) where Lg denotes a leaving group, for example, a halogen such as chloride, bromide or iodide, or an alkane- or an arenesulphonyloxy group such as the p-toluenesulphonylidene group, and Ri is C? -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, for example, K2C03, NaHCO3 or KOH, and at a reaction temperature. between +20 ° C and +150 ° C. (vii) Halogenation of the compound of formula IX to a compound of formula XII wherein Rc denotes bromide or iodide can be effected by a reagent such as IC1 or Br2 Cl2 or S02C12 with or without a suitable base such as sodium acetate in a suitable solvent such as acetic acid at a reaction temperature between +20 ° C and +50 ° C. (viii) the conversion of a compound of formula XII wherein Rc is a halogen, for example, bromide or iodide to a compound of formula XIII where Ri is C? -C6 alkyl or C3-Ce cycloalkyl, Re is C? alkyl? C6 (XII) (XIII) it can be carried out by palladium-catalyzed carbonylation. The process can be carried out by the reaction of XII with an alcohol of formula ReOH where Re is C? -C6 alkyl at atmospheric or elevated pressure with carbon monoxide in a suitable solvent such as dioxane or N, N-dimethylformamide and at the reaction temperature between +20 ° C and +120 ° C in the presence of a suitable catalyst such as PdX2, L2Pd (0), L2PdX2 where X denotes a halogen such as chloride or bromide or for acetate and L denotes a ligand suitable such as triphenylphosphine, 1,3-bis (diphenylphosphinopropane) or 1,1'-bis (diphenylphosphino) ferrocene and a suitable trialkylamine such as triethylamine. (iX) The conversion of a compound of formula XIII to a compound of formula XIV wherein Rx is dC6 alkyl or C3-C6 cycloalkyl and Rg is CONR6R7 wherein Re and R7 are H, C? -C6 alkyl or C3 cycloalkyl C6 can be executed through, a) hydrolysis under basic conditions with a suitable base such as KOH, LiOH or C2H5SNa in a suitable solvent such as methanol, tetrahydrofuran or N, N-dimethylformamide, in the presence of water at a reaction temperature of between 20 ° C and room temperature. reflux, or under acidic conditions in a suitable solvent such as methanol or ethanol using acids such as aqueous HBr, Hl, HBr / CH3COOH at a reaction temperature of between 20 ° C and reflux temperature, or cleavage with a Lewis acid such as BBr3 or TMSI in a suitable solvent such as methylene chloride or chloroform and at a reaction temperature between -78 ° C and +120 ° C. b) converting the acid formed above to an acid chloride with a suitable reagent such as S0C12 or (COCÍ) 2 neat or in a suitable solvent such as methylene chloride or chloroform with or without a catalytic amount of N, N-dimethylformamide a a reaction temperature between -20 ° C and the reflux temperature.

C) by reacting the hydrochloric acid with an excess of an amine of formula NHR6R7 where Re and R7 are H, C? -C6 alkyl or C3-C6-cycloalkyl in a suitable solvent such as methylene chloride or dioxane at a temperature of reaction between -20 ° C and reflux temperature. (x) The conversion of a compound of formula XIII to a compound of formula XV wherein Ri is C? -C6 alkyl or C3_C6 cycloalkyl can be performed by reduction with a suitable reducing agent such as LiAlH4 or LiAlH2 (OCH2CH2OCH3) 2 in a suitable solvent such as diethyl ether, tetrahydrofuran or toluene at a reaction temperature between + 20 ° C and the reflux temperature.

(XV) (xi) the conversion of a compound of formula XIV wherein R9 is CONR6R7 and R6 and R7 are H, C? -C6 or C3-C6 cycloalkyl to a compound of formula XVI wherein Ri is C? -C6 alkyl or cycloalkyl C3-C6 and Rg is CN or CONR6R where R6, v are H, Ci-Cß alkyl or C3-C6 cycloalkyl it can be carried out by splitting the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platinum or nickel in a suitable solvent, for example, acetic acid or ethanol, and the reaction can occur between + 20 ° C and +120 ° C or, by debenzylation using ammonium and palladium on carbon format in a suitable solvent such as methanol at a reaction temperature of between + 20 ° C and +65 ° C.

The conversion of a compound of formula XIV wherein Rg is C0NH2 to a compound of formula XVI wherein Rg is CN can be performed by a) debenzylation as described above followed by, b) dehydration with a suitable reagent such as S0C12 or P205 in a suitable solvent such as methylene chloride or toluene at a reaction temperature of between + 20 ° C and +110 ° C. (xii) the conversion of a compound of formula XV to a compound of formula XVI wherein Ri is Ci-Cß alkyl or C3-C6 cycloalkyl and Rg is methyl can be carried out by cleavage of the benzyl groups and reduction of the alcohols of benzyl under the conditions described in the above method xi in a suitable solvent such as acetic acid with or without a strong acid such as HCl or HBr. (xiii) The conversion of a compound of formula XII to a compound of formula XVII wherein R x is C 1 -C 6 alkyl or C 1 -C e cycloalkyl and R g is OH (XVII) it can be carried out by a metal-halogen exchange using an alkyl lithium or metal such as n-butylithium or lithium in a suitable solvent such as tetrahydrofuran or diethyl ether, followed by treatment with trimethyl borate, a peroxide acid such as peracetic acid or hydrogen peroxide and an acid such as acetic acid. The reaction can be carried out at a temperature between -78 ° C and + 20 ° C. (xiv) Conversion of a compound of formula XII to a compound of formula XVII wherein Rg is Ci-Cß alkyl or 3-C6 cycloalkyl or fluoride can be developed by metal-halogen exchange using a suitable alkyl lithium or metal such as n-butyllithium or lithium in a suitable solvent such as tetrahydrofuran or diethyl ether, followed by treatment with an alkyl halide such as methyl iodide or ethyl iodide by a fluorinating agent such as N-fluorobenzenesulfonimide and at the reaction temperature of between -78 ° C and the ambient temperature. (xv) The conversion of a compound of formula XVII to a compound of formula XVI Where Rg is Ci-Cß alkyl, C3-C6 cycloalkyl, F or OH can be carried out by debenzylation under the conditions described in method xi above . (xvi) The conversion of a compound of formula XVII wherein Rg is OH to a compound of formula XVI wherein R9 is C6-C6 alkoxide or 0CHF2 can be carried out by alkylation with a suitable alkylating agent such as an alkyl halide, for example, methyl iodide or ethyl iodide or chlorodifluoromethane, in the presence of a suitable base such as NaH, KOH or NaOH in a suitable solvent such as isopropanol, N, N-dimethylformamide or dioxane at a reaction temperature of between +20 ° C and +80 ° C followed by debenzylation under the conditions described in method xi above. (xvii) the conversion of a compound of formula IX to a compound of formula XVI wherein R9 is a halogen such as bromide, chloride or iodide can be carried out by debenzylation under the conditions described in the method xi described above followed by halogenation using a suitable reagent such as Br2, Cl2, S0C12 or Icl in a suitable solvent such as acetic acid, HCl / ethanol, methylene chloride or toluene with or without a suitable base such as sodium acetate at the reaction temperature of between -20 ° C and +20 ° C. (xviii) The conversion of a compound of formula XVI, to a compound of formula XVIII, where Ri is C? -C6 alkyl or C3-C6 cycloalkyl, R is H, C? -C5 alkyl and R9 is as in formula I above, can be carried out by (XVI) pcvi ») The acylation with an acetyloxycarboxylic acid azoate with formula R2C00H wherein R2 is H or C1-C5 alkyl in a suitable solvent such as methylene chloride or chloroform in the presence of a suitable base such as KOH, NaOH, K2C03 or a trialkylamine, by example, triethiamine.

Activation of carboxylic acid can be achieved through a) transformation of carboxylic acid into the corresponding acid chloride using a reagent such as SOCI2 or (C0C1) 2 in a suitable solvent such as methylene chloride or chloroform with or without a catalytic amount of N, N-ethylformamide at temperature of reaction between +20 ° C and +110 ° C. (xix) Conversion of a compound of formula XVIII to a compound of formula XIX wherein Ri is C? -C6 alkyl or C3-C6 cycloalkyl and R2 is C? -C6 alkyl can be carried out by reduction with a reducing agent Suitable such as lithium aluminum hydride or diborane in a suitable solvent such as diethyl ether, tatrahydrofuran or dioxane at a reaction temperature between + 20 ° C and the reflux temperature.

(XIX) (xx) The conversion of a compound of formula VIII to a compound of formula XX can be carried out with, for example, bis (2-chloroethyl) benzylamine or benzylaminodiacetic acid under the conditions described in method vi above. (xxi) Conversion of a compound of formula XX to a compound of Formula XXI wherein Rc is bromide, chloride or iodide can be carried out under the conditions described in method vii above.

(XX) (XXI) (xxi) The conversion of a compound of formula XXI to a compound of formula XXII where Rg is a) C 1 -C 6 alkyl or fluoride can be carried out by lithium-halogen exchange and reaction with an appropriate alkyl halide or a fluorinating agent under the conditions described in the method xiv above. b) CONR6R7 wherein R6 and 7 are C? -C6 alkyl or C3-C6 cycloalkyl can be carried out by the reaction of XXI with an excess of an amine of formula NHR6R7 wherein R6 and R? are as described above at atmospheric or elevated pressure with carbon monoxide using a suitable catalyst such as L2PdX2 where L denotes a suitable ligand such as triphenylphosphine or 1,1'-bis (diphenylphosphino) ferrocene and X denotes chloride, bromide or acetate, in a suitable solvent such as N, N-demethylformamide or dioxane and at a reaction temperature between + 20 ° C and +100 ° C. (xxiii) The conversion of a compound of formula XXII to a compound of formula XIII wherein Rg is Ci-C6 alkyl or fluoride and Rd is a suitable protecting group such as tert-butoxycarbonyl or benzoyloxycarbonyl can be carried out by (XXII) (XXIII) the debenzylation under the conditions described in method xi above followed by reaction with an educated acylating agent such as di-tert-butylcarbonate and a suitable base such as triethylamine in a suitable solvent such as methylamine chloride or chloroform and at a reaction between 0 ° C and +20 ° C. (xxiv) The conversion of a compound of formula XX to a compound of formula XXIII wherein Rg is a halogen such as bromide, chloride or iodide can be carried out by a) debenzylation under the conditions described in method xi above b) halogenation under the conditions described in method vii above c) protection under the conditions described in method xxiii above. 2. In the case where Y is CONR2 and X is N (i) the conversion of a compound of formula XXV to any racemate (described in: Thorberg, S-0, Hall, H .; Akesson, C; Svensson, K .; Nilsson, JLG Acta Pharm, Suec., 1987, 24 (4), 169-182) or as an enantiomer to a compound of formula XXXVI (? xv) (XXVI) it can be carried out by aromatic nucleophilic substitution using nitric acid in a suitable solvent such as acetic anhydride, methylene chloride or acetic acid at a reaction temperature between -20 ° C and room temperature. (ii) Conversion of a compound of formula XXVI, to a compound of formula XXVII, wherein Rg is methoxide, can be carried out by any hydrolysis under acidic conditions using acids such as H2SO4, HCl or HBr in a suitable solvent such as water, ethanol, methanol, acetic acid or mixtures of these and the reaction can occur at a temperature between +20 ° C and reflux or, under acidic conditions using bases such as KOH, NaOH or LiOH in a suitable solvent such as water , ethanol, methanol or mixtures of these and the reaction can occur at a temperature between +20 ° C and reflux. (iii) The conversion of a compound of formula XXVII to a compound of formula XXVIII wherein Y is CONR2 wherein R2 and R3 are defined in formula I above can be carried out by (XXVII) (XXVIU) a) activation of the carboxylic acid of formula XXVII under the conditions described in method 1, xviii above b) by reacting the acid chloride formed with an amine of formula NHR2R3 wherein R2 and R3 are as defined in formula I above , in a suitable solvent such as methylene chloride or chloroform in the presence of a suitable base such as trimethylamine or K2CO3 at a reaction temperature between -20 ° C and reflux temperature. (iv) the conversion of a compound of formula XVII to a compound of formula XXIX, wherein Rg is alkyl C? -C6, C? -C6 alkoxide, CONR6R7 where R6 and R7 are alkyl C? -C6 or cycloalkyl of C? -C6 and Y is C0NR where R2 and R3 are as defined in formula I above, can be carried out by (XXIX) reducing any nitro group using hydrogen at atmospheric or elevated pressure and a catalyst such as palladium, platinum or nickel in a suitable solvent such as methanol, ethanol or acetic acid at a reaction temperature between +20 and +120 ° C or by a reducing agent such as sodium dithionite or stannous chloride or ammonium formate and Pd / C in a suitable solvent such as methanol ethanol at a reaction temperature between +20 ° C and +80 ° C. (v) the conversion of a compound of formula XXVI to a compound of formula XXX can be carried out by demethylation under the conditions described in method 1, ii above. During the demethylation of XXVI the cleavage of the ester can occur and the carboxylic acid could in this case be re-esterified by methods known to a person skilled in the art. (vi) the conversion of a compound of formula XXX to a compound with formula XXXI where Re is Ci-Cß alkyl can be carried out by (XXX) (XXXI) reaction of XXX with a reagent such as trifluoromethanesulfonic anhydride or N- (2-pyridyl) triflimide and a suitable base such as triethylamine or lithium diisopropylamine in a suitable solvent such as methylamine or tetrahydrofuran chloride and at a temperature of reaction between -78 ° C and 0 ° C. (vii) The conversion of a compound of formula XXXI, to a compound of formula XXVI where the carboxylic acid has a protecting group Re and R9 is a) Ci-Cß alkyl, can be carried out by a STILLE-CUOPLING using an alkylating agent such as tetramethyltin and a suitable catalyst such as L2PdCl2 wherein L is a suitable ligand such as triphenylphosphine or 1, 1 ' -bis (diphenylphosphino) ferrocene in the presence of LiCl in a suitable solvent such as N, N-dimethylformamide or dioxane at a reaction temperature between +20 ° C and +100 ° C. c) CONR6R7 wherein R6 and 7 are C? -C6 alkyl or C3-C6 cycloalkyl, can be carried out by the reaction of XXXI with an excess of an amine of the formula NHR6R7 wherein R? and R7 are as described above at ambient or elevated pressure with carbon monoxide using a suitable catalyst such as L2PdX2 where L denotes a suitable ligand such as triphenylphosphine or 1,1-bis (diphenylphosphino) ferracene and X denotes chloride, bromide or acetate, in a suitable solvent such as N, N-dimethylformamide or dioxane at a reaction temperature between +20 ° C and +100 ° C. (vii) the conversion of. a compound of formula XXXI to a compound of formula XXXII can be carried out by (XXXII) a) the reduction under the conditions described in method 1, xi above b) benzylation under the conditions described in method l, i above c) hydrolysis of the ester under the conditions described in method 1, ix above. (ix) the conversion of a compound of formula XXXII to a compound of formula XXIX wherein R9 is a halogen such as bromide or chloride is developed by a) activation of the carboxylic acid under the conditions described in method 1, xviii above b) the reaction with an amine of the formula NHR2R3 wherein R2 is hydrogen or C? -C6 alkyl / R3 is C? -C6 alkyl C3-C? cycloalkyl or (CH2) n-aryl, where the aryl is phenyl or a heterocyclic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and / or R5; wherein R4 is hydrogen Ci-Ce alkyl, phenoxide, C? -C6 alkylphenyl, an optionally substituted heterocycle or heteroatom ring containing one or two heteroatoms selected from N, 0, S, S02 wherein the substituent (s) ) is (are) selected from C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, phenyl C 1 -C 6 alkyl; wherein R 6 and R 7 are hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein R 5 is hydrogen, OH, F, CF 3, C 1 -C 6 alkyl or C 2 -C 6 cycloalkyl; and n is 0-4 c) debenzylation under the conditions described in method 1, xi above d) halogenation under the conditions described in method vii above. 3. In the case where Y is NR2CO and X is CH (i) the conversion of a compound of formula XXV to a compound of formula XXXIII can be developed by an aromatic nucleophilic substitution using a halogenating agent such as Br2 or n-bromosuccinimide and a suitable base such as sodium acetate in a solvent suitable such as acetic acid and at a reaction temperature between 0 and + 20 ° C. (ii) the conversion of a compound of formula XXXIII to a compound of formula XXXIV can be developed by (xxxi ") (XXXIV) a) hydrolysis of the ester under the conditions described in method 1, v above b) a skin rearrangement by converting the carboxylic acid to an acyl azide with a suitable reagent such as SOCL2 and a suitable base such as trimethylamine in a suitable solvent such as methylamine chloride or toluene followed by heating to the acid chloride formed with azide of sodium or by reacting the carboxylic acid with diphenoxyphosphoric azide in a suitable solvent such as methanol or refluxing water. If the methanol is used as the solvent the carbamate formed can be hydrolyzed to an amine under the conditions described in method 1, v above. (iii) The conversion of a compound of formula XXXIV to a compound of formula XXXV can be developed by benzylation under the conditions described in method 1, i above. (iv) Conversion of a compound of formula XXXV to a compound of formula XXXVI wherein R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl can be developed by (XXXV) (XXXVI) a) a halogen metal exchange using an alkyl lithium or a metal such as n-butyl lithium, lithium or magnesium followed by treatment with a suitable N-alkyl-piperidone such as N-methyl-piperidone in a suitable solvent such as tetrahydrofuran or diethyl ether at a reaction temperature between 78 ° C and 0 ° C b) reduction of the benzyl alcohol formed by a suitable reducing agent such as sodium borohydride or triethylamine and an acid such as CF3C02H or CF3S03H in a suitable solvent such as tetrahydrofuran or diethyl ether at a reaction temperature between 0 ° C and +65 ° C. (v) The conversion of a compound of formula XXXVI to a compound of formula XXXVII wherein Rx is Ci-Ce alkyl or C3-C6 cycloalkyl can be developed by a) Demethylation under the conditions described in method 1, ii above b) TRIFLATING the phenol formed under the conditions described in method 2, xxx above. (vi) the conversion of a compound of formula XXXVI to a compound of formula XXXVIII wherein R9 is a) C 1 -C 6 alkyl, can be carried out by a stabilizing coupling under the conditions described in method 2, vii-a b) C 0 NR 6 R 7 wherein R 6 and 7 are C 1 -C 6 alkyl or C 3 cycloalkyl -C6, can be developed by palladium-catalyzed carbonylation under the (xxxvii) poxviu) conditions described in method 1, xxii-b. (vii) the conversion of a compound of formula XXXVI to a compound of formula XXXVIII wherein Rg is a) methoxide, can be developed by debenzylation under the conditions described in method 1, xi above. b) idroxil, can be developed by demethylation under the conditions described in method 1, ii above followed by debenzylation as described in method 1, xi above. c) C2-C6 alkoxide or 0CHF2, can be developed by demethylation as described in method 1, ii above followed by alkylation under the conditions described in method 1, xvi and debenzylation as described in method 1, xi from above. (viii) The conversion of a compound of formula XXXVIII to a compound of formula XXXIX wherein R9 is Ci-Cß alkyl, C?-C6 alkoxide, 0CHF2 or hydroxide and R2 is Ci-Cß alkyl, can be developed by (XXXIX) a) amidation of XXXVIII with a carboxylic acid of formula R2CoCH wherein R2 is hydrogen or C? -C5 under the conditions described in method 1, xviii above b) reduction under the conditions described in method 1, xix above. (ix) The conversion of a compound of formula XXXVII to a compound of formula XL where Ri is C? -C6 alkyl or C3-C6 cycloalkyl and Re is C? -C6 alkyl can be developed under the conditions described in method 1, viii above.

(XL) the conversion of a compound of formula XL to a compound of XXXVIII where R? is C? -C6 alkyl or C3-C6 cycloalkyl and Rg is CN can be developed by a) amidation with NH3 under the conditions described in method 1, ix above b) dehydration of the primary amide and debenzylation under the conditions described in method 1, xi above.

Method of Preparation of Final Products Another object of the invention is a process A (i), A (ii), A (iii), B (i), B (ii), C (i), C (ii), D or E for the preparation of the compounds of general formula I by Ai) Acylation, in the case where Rx is Ci-Ce alkyl or C3-C6 cycloalkyl, Y is NR2C0, R2 is hydrogen and, R3 and Rg are as defined in general formula I above, of a compound of general formula TO (A) (I) With an activated carboxylic acid R3-C0Lg? where Lgi is a leaving group or by the use of a carboxylic acid R3-C00H with an activating reagent.

So, acylation. According to process A (i) it can be carried out with an appropriate activated carboxylic acid, R3COLg? where R3 is as defined above and Lgi is a leaving group, such as a halogen, for example chloride, in a suitable solvent such as methylene chloride or chloroform with a suitable base, for example, a trialkylamine such as triethylamine, at a temperature between -20 ° C and the reflux temperature or by using a carboxylic acid R3COOH wherein R3 is as defined above with an activating reagent, for example, N, N-carbonyldiimidazole, N, N-dicyclohexylcarbodiimide or chloride diphenylphosphoric, with a suitable base such as N-methylmorpholine in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran and the reaction can be conducted at a temperature of between + 20 ° C and +150 ° CMethod A (ii) Acylation in the case where R? is C? -C6 alkyl, Y is NR2C0, R2 is C? -C6 alkyl, and X, R3 and R9 are as defined in general formula I above, of a compound of formula B, With an activated carboxylic acid R3-COLg? where Lgi is a leaving group or by the use of a carboxylic acid R3-COOH with an activating reagent.

Thus the acylation according to process A (ii) can be carried out with an appropriate activated carboxylic acid, R3COLg? where R3 is as defined above and Lgx is a leaving group, such as halogen, for example chloride, in a suitable solvent such as methylene chloride or chloroform with a suitable base for example, trialkylamine such as triethylamine at a temperature of between 320 ° C and the reflux temperature or by the use of a carboxylic acid R3COOH wherein R3 is as defined above with an activating reagent, for example N, N'-carbonylmethyldimidazole, N, N'-dicyclohexylcarbodiimide or diphenylphosphinic chloride, with a suitable base such as N-methylmorpholine in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran and the reaction can be conducted at a temperature between +20 ° c and +150 ° C.

Method A (iii) Acylation, in the case where Ri and R2 are hydrogen, and is NR2C0, Rd is a protecting group and X, R3 and Rg are as defined in general formula I above, for a compound of formula C (C) (D With an activated carboxylic acid R3-COLg? Where Lgx is a leaving group or by the use of a carboxylic acid R3-COOH with an activating reagent, followed by removal of the protective group Rd.

Thus, acylation according to process A (iii) can be carried out with an appropriate activated carboxylic acid, R3COLg? where R3 is as defined above and Lgi is a leaving group, such as a halogen, for example chloride, in a suitable solvent such as methylene chloride or chloroform with a suitable base, for example trialkylamine such as triethylamine or by use of a carboxylic acid, R3 COOH where R3 is as defined above, with an activating reagent, for example N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or defensilphosphinic chloride, with a suitable base such as N-methylmorpholine in a suitable solvent such as N, N'-deimethylformamide or tetrahydrofuran and the reaction can be conducted at a temperature between + 20 ° C and +150 ° C, followed by removal of the protecting group Rd by hydrolysis in a suitable solvent such as Methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature between +20 ° C and +60 ° C.

Method B (i) The reaction in the case where Y is CONR2, R2, R3 and Rg are as defined in general formula I above, a compound of formula D s »a > with a compound of formula XI wherein Lg is a leaving group.

Thus, the reaction according to process B (i) can be carried out with a compound of formula XI wherein Rx is as defined in general formula I and Lg is a leaving group, for example a halogen such as chloride, bromide or iodide, or an alkane- or an arenesulfonyloxy group such as the p-toluenesulphonyloxy group. The process can be carried out in a suitable solvent such as acetonitrile with or without a suitable base, for example K2C03, NaHCO3 or KOH, and the reaction can occur between +20 ° C and +150 ° C.

Method B (ii): The reaction in the case where Y is C0NR2, R is H, R2, R3 and R9 are as defined in general formula I above with the exception of when R4 and Rg are substituents that are susceptible to undergoing known catalytic hydrogenation by a person skilled in the art, a compound of formula D (D) (I) With a compound of formula XLI wherein Lg is a leaving group.

Thus, the reaction according to process B (ii) can be carried out with a compound of formula XLI where Lg is a leaving group, for example, a halogen such as chloride, bromide or iodide, or an alkane- or a group arenesulfonyloxide. 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, for example. K2C03 or KOH, and the reaction can occur between +20 ° C and 150 ° C followed by removal of the benzyl group by catalytic hydrogenation at atmospheric or elevated pressure using a catalyst such as palladium, platinum or nickel in a solvent Suitable such as methanol, ethanol or acetic acid with or without an acid such as HCl or HBr at a reaction temperature of between +320 ° C and +100 ° C.

Method C (i): The reaction in the case where Y is NR2S02, R2 is hydrogen, Ri, R3 and R9 are as defined in the general formula I above, of a compound of formula E With an appropriate activated sulfonic acid R3S02Lg ?, where Lgi is a leaving group such as a halogen, for example, chloride, in a suitable solvent such as methylene chloride or chloroform with a suitable base, for example a trialkylamine such as triethylamine, and the reaction can be conducted at a temperature between -20 ° C and +60 ° C.

Method C (ii): The reaction, in the case where y is NR2S02, R2 is Ci-Ce alkyl, Ri, R3 and R9 are as defined in general formula I above, of a compound of formula E ÍEi (I) With an appropriate activated sulfonic acid R3S02Lg ?, where Lgi is a leaving group such as a halogen, for example, chloride, in a suitable solvent such as methylene chloride or chloroform with a suitable base, for example a trialkylamine such as triethylamine, and the reaction can be conducted at a temperature between -20 ° C and +60 ° C.

Method D: The reduction, where Y is NR2CH2 or CH2NR2, and X, Rlf R2, R3 and Rg are as in formula I above with the exception of when R4 and R9 are substituents that are susceptible to certain reducing reagents known to a skilled person in the ethnic one, of a compound of formula I above where Y is NR2C0 or C0NR2, and X, Ri, R2, R3 and R9 are as in (I) formula I above, It can be carried out with an appropriate reducing agent such as lithium aluminum hydride, borane or borane dimethylsulfide in a suitable solvent, for example, diethyl ether, dioxane or tetrahydrofuran, at a temperature between + 20 ° C and the temperature of Reflux.

Method E: The alkylation, in the case where R? is C? -C6 alkyl, C3-C6 cycloalkyl, and is NR2CH2 and X, R2, R3 and R9 are as defined in general formula I above with the exception of when R4 and R9 are substituents that are susceptible to certain alkylations known to a person skilled in the art, of a compound of formula B It can be carried out with an appropriate alkylating agent.

Thus, the alkylation can be carried out with an alkylating agent of formula R3Lg where Lg is a leaving group, such as a halogen, for example, chloride, bromide, or iodide, or an alkane or arenesulfonyloxy group, such as the group p -toluenesulfonyloxide, in the presence of a base such as triethylamine or K2C03 and the reaction can be developed in a suitable solvent such as acetonitrile or N, N-dimethylformamide and at a reaction temperature between +20 ° C and +100 ° C or by reductive alkylation with an aldehyde of formula R3CH0 and a reducing agent such as sodium cyanoboride in a suitable solvent such as methanol or tatrahydrofuran or a mixture thereof and adjustment of pH to slightly acid by an acid such as acetic acid and the reaction It can be developed at a temperature between +10 ° C and +50 ° C.

Intermediaries The present invention also relates to new intermediaries, named intermediates of formulas where X is N or CH; R x is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R2 is hydrogen or C? -C6 alkyl; R9 is Ci-Ce alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, C? -C6 alkoxide, C? -C6 alkoxide, C? -C6 alkyl. NR6R7, S03CH3, S03CF3, S02NR6R7, a substituted or unsubstituted heterocyclic or heteroatom ring containing one or two heterotomes selected from N and 0, wherein the substituent (s) is (are) Ci-Cß alkyl; or C0R8; wherein R 6 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R7 is H, C? -C6 alkyl or C3-C? Cycloalkyl; and Re is C3-C6 alkyl C3-C6 cycloalkyl, CF3, NR6R7, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, 0 and S or a heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO and S02 where Re and R7 are as defined above; where X is N; R9 is as defined above; Rd is a protective group; Y where Y is CONR2; R 2 is hydrogen or C 1 -C 6 alkyl; R3 is as defined above; and Rg is as defined above.

The invention is illustrated but not restricted in the following examples.

Work examples Example 1 (S) -3-N, N-Dibenzylamino-% methoxy-3,4-dihydro-2H-l-benzopyran hydrochloride.

(S) -3-N, N-Dibenzylamino-methoxy-3, -dihydro-2H-l-benzopyran (45 g, 0.25 mol, described in WO93 / 07135), K2C03 (120 g, 0.87 mol) and benzyl bromide ( 65 ml, 0.55 mol) were mixed in acetonitrile (1000 mL) under nitrogen. The reaction mixture was partitioned between diethyl ether and saturated NaCl (aq). The phases were separated and the organic phase was dried (MgSO4) and filtered followed by precipitation of the hydrochloric salt at room temperature. Obtaining: 99 grams (99%). An analytical sample was transferred to the base: [a] 21D + 116 ° (c 1.0, chloroform). EIMS (70 eV) m / z (relative intensity) 359 (28, M +).

Example 2 (s) -3-N, N-Dibenzylamino-5-hydroxy-3,4-dihydro-2H-l-benzopyran.

(S) -3-N, N-Dibenzylamino-5-methoxy-3,4-dihydro-2h-l-benzopyran hydrochloride (67 g, 0.17 mol) were dissolved in methylene chloride (500 mL) under nitrogen, and the solution was cooled to +75 ° C. Boron tribromide (32 mL, 0.34 mol) was added as drops for 5 minutes. The temperature was then allowed to slowly reach + 5 ° C, and the reaction mixture was stirred overnight. The reaction mixture was carefully cooled with a 2M aqueous NH 3 solution under stirring. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The organic phases were combined, washed with brine, dried (MgSO 4), filtered and the solvent was removed in vacuo to give a brownish residue oil which was purified by flash chromatography on a column of silica gel using methylene chloride as eluent . Obtaining 50 g (86%) of the title compound: [a] 21D + 109 ° (c 1.0, chloroform). EIMS (70 eV) m / z (relative intensity) 345 (5, M +).

Example 3 (s) -2- (3-N, N-Dibenzylamino-3,4-dohydro-2H-l-benzopyran-5-yloxy) -2-methylpropanamide.

The (s) -3-N, N-Dibenzylamino-5-hydroxy-3,4-dihydro-2H-l-benzopyran (50 g, 0.14 mol) were dissolved in anhydrous 1,4-dioxane (45 mL). nitrogen. A dispersion of sodium hydride (60-65% in oil, 6.1 g, 0.15 mol) was added in portions. The mixture was stirred by Ih at room temperature, 2-Bromo-2-methylpropanamide (24 g, 0.14 mol, Coutts, IG C; Southcott, MR j.Chem. Soc. Perkins Trans. 1 1990, 767-771) It was added to the dark greenish solution and heated to reflux with stirring for 3 h. An additional amount of sodium hydride (60-65% in oil, 2.8 g, 70 mmol) and 2-bromo-methylpropanamide (4.6 g, 28 mmol) were added in portions and heating to 60 ° C was continued by 17 h. After cooling a small amount of methanol (10 mL) was added and the solution was filtered and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (500 mL) and saturated NaHCO3 solution (50 mL). The organic phase was dried (MgSO 4), and the solvent was removed in vacuo to give a brownish residue which was crystallized from ethyl acetate / hexane. Obtained: 45 g (71%) of the title compound as a white solid: mp 133-134 [a] 21D + 99 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 430 (9, M +).

Example 4 (S) -5-Amino-3-N, N-dibenzylamino-3,4, dihydro-2H-l-benzopyran.

To a solution of (S) -2- (3-N, N-dibenzylamino-3, -dihydro-2H-l-benzopyran-5-yloxy) -2-methylpropanoamide 846 g, 0.11 mol) in N, N-dimethylformamide anhydrous (450 mL) and 1,3 dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (45 mL) was added sodium hydride (60-65% in oil, 8.5 g, 0.21 mol) in portions under nitrogen. The reaction mixture was heated to 110 ° C with stirring for 13 h. The mixture was then allowed to cool, and the solution was partitioned between ethyl acetate (400 mL) and a 2M solution of NH3 (200 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (150 mL). The combined organic phases were dried (gS04) and concentrated in vacuo to give a brownish oil. EIMS (70 eV) m / z (relative intensity) 430 (3, M +).

The material obtained (0.11 mmol) was dissolved in methanol (350 mL). A 6 M solution of HCl (250 ml) was added, and the reaction mixture was heated to reflux for 16 h. After stirring, the reaction mixture was allowed to cool to 35 ° C, the ethanol solvent was removed in vacuo, and ethyl acetate was added to the aqueous retentate. The mixture was cooled on ice, and a solution of NH3 conc. It was slowly added with agitation. The layers were separated, and the organic phase was extracted with another portion of ethyl acetate. The combined organic phases were dried (MgSO4), and the solvent was removed in vacuo to give a brownish oil which was purified on a short column of silica gel (eluent hexane / ethyl acetate 8: 2) yielding 25 g (68 g). % yield) of the desired compound as a slightly yellow oil. The product crystallized slowly by staying in the refrigerator. An analytical sample was recrystallized from diethyl ether (petroleum ether: mp 101-103 ° C [a] 21D + 123 ° (c 1.0, chloroform), EIMS (70 eV) m / z (relative intensity) 344 (17 , M +).

Example 5 (S) -1- (3-N, N-Dibenzylamino-3,4-dihydro-2H-l-benzopyran-5-yl) -4-methylpiperazine-2,6-dione. To a dispersion of acid N-Methyliminodiacetic acid (6.90 g, 46.9 mmol) in anhydrous tetrahydrofuran (575 mL) was added with 1,1'-carbonyldiimidazole (15.2 g, 93.9 mmol), and the mixture was heated at reflux for 2 h under nitrogen. A solution of (S) -5-amino-3-N, N-dibenzylamino-3,4-dihydro-2H-l-benzopyran (15.0 g, 42.7 mmol) in tetrahydrofuran (120 mL) was added with stirring for 0.5 h . The reaction mixture was heated to reflux for 28 h, then allowed to cool, and the solvent was removed in vacuo. The residue was purified on a short column of silica gel (eluent: methylene chloride and ethyl acetate) to give 14.1 g (71% yield) of the title compound as a slightly yellow solid :: mp sinter > 60 ° C [a] 21D + 89 ° C (c 1.0, chloroform). EIMS (70 eV) m / z (relative intensity) 455 (8, M +).

Example 6 (S) -3-N, N-Dibenzylamino-5- (α-methylpiparazin-1-yl) -3,4-dihydro-2H-benzopyran. To a stirred solution of (S) -l- (3-N, N-dinencylamino-3,4-dihydro-2H-1-benzopyrano-5-yl) -4-methylpiperazine-2,6-dione (25.4 g, 55.8 mmol) in diethyl ether (800 mL) was added lithium aluminum hydride (9.30 g, 246 mmol) in portions. The reaction mixture was heated to reflux for 6.5 h under nitrogen overnight at room temperature. The mixture was cooled (ice bath), and water (10 mL) was added followed by a 15% aqueous solution of NaOH (10 mL) and another portion of water (30 mL). The precipitate was filtered and washed with several portions of hot tetrahydrofuran. The combined organic phases, and the solvent was removed in vacuo. The residue was purified by a silica chromatography column (eluent: chloroform / ethanol; 95; 5 + 0.5% conc NH3) giving 13.6 (57% yield) of the title compound as a slightly yellow oil: ] 21D + 63 ° (c 1.0, chloroform). EIMS (70 eV) m / z (relative intensity) 427 (5, M +).

Example 7 (S) -3-N, N-Dibenzylamino-8-iodo-5-4-m, ethylpiperazin-1-yl) -3,4-dihydro 2H-l-benzopyran (S) -3-N, N-Dibenzylamino-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzo-1-pyran (6.9 g, 16 mmol) and sodium acetate ( 1.5 g, 18 mmol) were dissolved in acetic acid (430 mL). To the solution was added iodine monochloride (18 mL 1 M, 18 mmol) and the reaction mixture was stirred at room temperature, while protected from light, for 24 h. Additional iodine monochloride (2.5 mL, 1M, 2.5 mmol) was added followed by stirring for 3 h. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride (800 mL) and 2M NaOH (120 mL). The aqueous phase was extracted with methylene chloride (100mL) and the combined organic phases washed with brine (2x100 mL) and dried (MgSO4). Evaporation of the solvent gave 8.6 g of crude product. Purification by a chromatography column using ethyl acetate / ethanol (saturated with ammonia) (25: 1) as the eluent gave 4.1 g (43% yield) of the title compound (containing about 7% starting material) as a yellowish solid: EIMS (70 eV) m / z (relative intensity) 537 (15, M +). The product was used in the next step without trying to purify it later.

Example 8 (S) -8-Methoxycarbonyl-3-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) -3,4-dihydro 2H-1-benzopyran (s) -3-N, N-dibenzylamino -8-iodo-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (2.6 g, 4.8 mmol) was dissolved in N, N-dimethylformamide (100 mL) and filled with monoxide. of carbon. To the solution was added palladium acetate (110 mg, 0.48 mmol), 1,3-bis (diphenylphosphino) propane (200 mg, 0.48 mmol), methanol (25 mL) and triethylamine (3.3 mL, 24 mmol). The mixture was reacted with carbon monoxide at 90 ° C and at atmospheric pressure for 8 h. The solution was filtered, the solvent was evaporated. The residue was co-evaporated with xylene (2x 50 mL) and partitioned between methylene chloride (300 mL) and 2 M NH3 (50 mL). The aqueous phase was extracted with methylene chloride (50 mL) and the combined organic phases were washed with brine (2x50 mL) and dried (MgSO4). The solvent was evaporated giving 4.0 g of a crude product. Purification by a silica chromatography column using methylene chloride / ethanol (saturated with ammonia) (1:50) as the eluent gave 1.7 g (68% yield) of the title compound (containing about 5% of the corresponding 8-H analog) as a yellowish solid: EIMS (70 eV) m / z (relative intensity) 485 (8, M +). The product was used in the next step without attempting to purify it later.

Example 9 (S) -3-N, N-Dibenzymamino-8-hydroxymethyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-benzopyran (S) -8-Methoxycarbonyl-3-N, N-dibenzylamino-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (490 mg, 1.0 mmol) was dissolved in dry tetrahydrofuran. (40 mL) and lithium aluminum hydride (76 mg, 2.0 mmol) was added in portions. The reaction mixture was stirred at 45 ° C for 4 h and cooled to room temperature. The reaction was cooled by the addition of water (76 μL), 15% NaOH and water (225 μL) and stirred for 18 h. The white precipitate was filtered and the solution and the solution was dried (MgSO). The solvent was evaporated in vacuo to give 520 mg of a crude product. Purification by a silica chromatography column using chloroform ethanol (saturated with ammonia) (15: 1) as eluent gave 390 mg (85% yield) of the title compound (containing about 8% of the corresponding 8-methyl analogue ) as a yellowish oil: EIMS (70 eV) m / z (relative intensity) 457 (815 M +).

Example 10 (S) -3-Amino-8-, ethyl-5- (4-methylpiperazin-1-yl) -3,4-dihydro-1-benzopyran (S) -3-N, N-Dibenzylamino-8-hydroxymethyl-5- (4-methylpiperazin-1-yl) -. 3, 4-dihydro-2H-1-benzopyran (420 mg, 0.90 mmol) was dissolved in methanol (60 mL) and ammonium formate (460 mg, 7.3 mmol) were added. The solution was filled with nitrogen and palladium on carbon (120 mg, 10%) were added. The reaction mixture was stirred at 50 ° C for 16 h. The catalyst was filtered and the solvent was evaporated in vacuo giving 260 mg of a crude product. The residue was dissolved in acetic acid (50 mL) and palladium on charcoal (120 mg, 10%) was added. The reaction mixture was hydrogenated at room temperature and at atmospheric pressure for 46 h. The catalyst was filtered and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (120 mL) and 2M NaOH (10 mL) and the aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with. brine (5 mL), dried (MgSO 4) and the solvent was evaporated in vacuo giving 200 mg of a crude product. Purification by preparative TLC on silica using chloroform / ethanol (saturated with ammonia) (10: 1) as eluent giving 150 mg (64% yield) of the title compound as an oil: EIMS (70 eV) m / z (intensity relative) 261 (100, M +).

Example 11 S (S) -N- [8-Methyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2 H -l-benzopyran-3-yl] -4-methylbenzamide 4-Methylbenzoic acid (22 mg, 0.16 mmol) and 1,1'-carbonyldiimidazole (27 mg, 0.17 mmol) were dissolved in dry N, N-dimethylformamide (2 mL) and stirred at 75 ° C for 1 h. The reaction mixture was cooled to room temperature and a solution of (S) -3-amino- (methyl-5- (methyl-piperazin-1-yl) -3, -dihydro-2H-l-benzopyran (40 mg, 0.15 mmol) dissolved in dry N, N-dimethylformamide (4 mL) was added. The reaction mixture was stirred at room temperature for 4 days and the solvent was evaporated in vacuo. The crude material was partitioned between methylene chloride (40 mL) and 10 mL water). The organic phase was washed with water (10 mL) and brine (15 mL) and dried (MgSO 4). The solvent was evaporated in vacuo yielding 48 mg of a crude product. Purification by preparative TLC on silica using chloroform / ethanol (saturated with ammonia) (15: 1) as eluent gave 23 mg (40% yield) of the title compound as a white solid: mp 191-192 ° C; EIMS (70 eV) m / z (relative intensity) 379 (100;, M +): [a] 21D -7 ° (c 0.10, chloroform). Example 12 (S) -8-Carbamoyl-3-N, N-dibenzylamino-5- (4) methylpiperazin-1-yl) -3,, 4-dihydro-2H-l-benzopyran (S) -8-Methoxycarbonyl-3-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (800 mg, 1.6 mmol) and potassium hydroxide (500 mg, 8.9 mmol) were dissolved in methanol (50 mL) and stirred at 65 ° C for 3 days. The solvent was evaporated in vacuo and the residue coevaporated with toluene (2x 100 mL) to give 1.2 g of a crude material. The solid was dispersed in methylene chloride (40 mL) and thionyl chloride (1.2 mL, 16 mmol) were added. The reaction mixture was heated to reflux for 1 H followed by evaporation with toluene (100 mL) and drying in vacuo. The crude acid was mixed with methylene chloride (40 mL) and cooled in ice. Concentrated ammonia (5 mL), 65 mmol) was added and the reaction mixture was stirred at about 0 ° C for 20 min and at room temperature for 40 min. Methylene chloride (100 mL) and water (50 mL) were added and the aqueous phase was extracted with methylene chloride (30 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO 4) followed by evaporation of the solvent in vacuo to give 790 mg of a crude product. Purification by preparative TLC on silica using chloroform ethanol (saturated with ammonia) (15: 1) as the eluent gave 460 mg (50% yield) of the title compound as white crystals: mp 173-174 ° C; EIMS (70 eV) m / z (relative intensity) 470 (4, M +).

Example 13 (S) -3-Amino-8-carbamoyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (S) -8-Carbamoyl-3-N, N -dibencialmino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (120 mg, 0.95 mmol) was dissolved in methanol (40 ml) and palladium on charcoal (480 mg 10%) was added.The bottle was filled with nitrogen, ammonium formate (480 mg, 7.6 mmol) were added and the reaction mixture was stirred at 50 ° C for 18 h. The catalyst was filtered and the solvent was evaporated in vacuo.The residue was co-evaporated with toluene and dried in vacuo to give 300 mg (100% yield) of the title compound: EIMS (70 eV) m / z (relative intensity ) 290 (100, m +) The raw product was used in the next step without attempting to purify it later.

Example 14 (S) -N- [8-Carbamoyl-5- (4-methyl-piperazin-1-yl) -3,, 4-dihydro-2H-l-benzopyran-3-yl] -4-benzoylbenzamide 4-Benzoylbenzoic acid (800 mg, 1.6 mmol) and 1,1'-carbonyldiimidazole (71 mg, 0.44 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at 75 ° C for 1 h. The reaction mixture was cooled to room temperature and a solution of (S) -3-Amino-8-carbamoyl-5- (4-methylpiperazin-1-yl) -3, -dihydro-2H-1-benzopyran (120 mg, 0.40 mmol) in N, N-dimethylformamide was added. The reaction mixture was stirred at room temperature for 4 days and the. The solvent was evaporated in vacuo giving 290 mg of a crude product. Purification by preparative TLC on silica using Chloroform / ethanol (saturated with ammonia) (15: 1) as eluent gave 75 mg (38% yield) of the title compound: mp 259 ° C (dec); EIMS (70 eV) m / z (relative intensity) 498 (38, M +); [a] 21D -3 ° (c 0.1 chloroform).

Example 15 (S) -N- [8-Methyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (dimethylaminocarbonyl) benzamide (Dimethylaminocarbonyl) enzoic (described in: Jurewitcz, A. T; US patent 3,607,918, 1971) (38 mg, 0.20 mmol) and 1,1 '-carbonidldiimidazole (34 mg, 0.21 mmol) were dissolved in dry N, N-dimethylformamide. (4mL) and stirred at 75 ° C for 15 h. The reaction mixture was cooled to room temperature and a solution of (S) -3-amino-8-methyl-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-l- was added. benzopyran 849 mg, 0.19 mmol) in dry N, N-dimethylformamide (5 mL). The reaction mixture was stirred at 50 ° C for 14 h and the solvent was evaporated in vacuo to give 120 mg of a crude product. Purification by preparative TLC using chloroform / methanol NH3 conc (95: 5: 0.5) as eluent gave 40 mg (48% yield) of the title compound as a white foam: EIMS (70 eV) m / z (relative intensity) 436 (26, M +); [a] 21D -9 ° (c 0.20, chloroform).

Example 16 Acid ethyl ester 8-Methoxy-5-nitro-3, 4-dihydro-2H-l-benzopyran-3-carbocyclic.

To a stirred solution of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (described in Thorberg, S-0 et al., Acta Pharm, Suec, 1987, 24, (4 ), 169-182) (5.5 g, 23 mmol) in methylene chloride (5 mL) at 0 ° C were added in the form of 65% HN03 drops (2.0 mL). The solution was stirred at room temperature for 2 h and washed with water. The organic phase was dried and the solvent was evaporated in vacuo. The residue was treated with diisopropyl ether and ethyl acetate (5 mL) to give 1.5 g (5.3 mmol) of crystals of the 6-nitro isomer. The mother liquor was purified by a chromatography column using disiisopropylether as eluent to give 1.3 g (20% yield) of the title compound: mp66-68 ° C; EIMS (70 eV) m / z (relative intensity) 281 (100, M +).

Example 17 8-Methoxy-5-notro-3,4-dihydro-2H-l-benzopyran-3-carboxylic acid.

A mixture of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (5.8 g, 21 mmol) in ethanol (150 mL) and 2 M NaOH (15 mL) ) was heated to reflux for 30 min. the solvent was evaporated in vacuo the residue dissolved in water. Acidification to pH 2 and extraction with ethyl acetate followed by evaporation of the solvent in vacuo gave 4.9 g (94% yield) of the title compound: mp 181-183 ° C; EIMS (70 Ev) m / z (relative intensity) 253 (55, M +).

Example 18 N- (4-Morpholinophene) -5-amino-8-methoxy-3,4-dihydro-2H-l-benzopyran-3-carboxamide.

To a solution of 8-methoxy-5-nitro-3,4-dihydro-2h-1-benzopyran-3-carboxylic acid (2.5 g, 10 mmol) in toluene (40 mL) and N, N-dimethylformamide (1 mL) ) thionyl chloride (3.6 mL), 50 mmol) was added. The reaction mixture was refluxed for 2 h and the solvent was removed in vacuo. The residual acid chloride was added to a solution of 4- (1-morpolino) aniline (described in Devlin, J. P. et al., J. Chem. Soc. Perkin trns, 1. 1975 830-841) (1.78 g, 10 mmol) and triethylamine (2.0 g, 20 mmol) in methylene chloride (30 mL) and stirred at 0 ° C for 10 min and for 1 h at room temperature. The solvent was removed in vacuo and the resident was dissolved in ethyl acetate and washed with 2M NaOH. Evaporation of the solvent in vacuo gave 1.5 g (35% yield) of the title compound as white crystals: mp 238-240 ° C; EIMS (70 eV) m / z (relative intensity) 413 (5, M +).

Example 19 N- (4-morpholinophenyl) -5-amino-8-methoxy-3,4-dihydro-2H-l-benzopyran-3-carboxamide.

To a solution of N- (4-morpholinophenyl) -8-methoxy-5-nitro-3, -dihydro-2H-1-benzopyran-3-carboxamide (1.2 g, 2.9 mmol) in N, N-dimethylformamide (10 L ) a solution of sodium dithionite (2.1 g, 12 mmol) in water (5 mL) was added. The mixture was stirred at 55 ° C for 3 h and the solvent was removed in vacuo. The residue was purified by a silica gel chromatography column using ethyl acetate as eluent to give 273 mg of the title compound (55% yield); EIMS (70 eV) m / z / (relative intensity) 383 (100 M +).

Example 20 N- (4-Morpholinophenyl) - (methoxy-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-carboxamide.

To a solution of N- (4-morpholinophenyl) -5-amino-8-methoxy-3,4-dihydro-2H-l-benzopyran-3-carboxamide (270 mg, 0.7 mmol), bis (2-chloroethyl) hydrochloride ) -methylamine (288 mg, 1.5 mmol) and sodium hydrogen carbonate (126 mg, 1.5 mmol) in n-butanol (10 mL) was stirred at 90 ° C for 2.5 h, 2M ammonia (10 mL) was added at 50 ° C, the mixture was cooled and the phases were separated. The organic phase was evaporated in vacuo and the residue was purified by a column chromatography on silica gel using ethyl acetate / triethylamine (100: 8) as eluent giving 170 mg (50% yield) of the title compound as white crystals: mp 202-204 ° C; EIMS (70 eV) m / z (relative intensity) 466 (100, M +).

PHARMACOLOGY Magnetic Field Stimulation of [3H] -5-HT-released from the occipital cortex of guinea pigs [3H] -5-HT is released by electric field stimulation of cuts of the guinea pig occipital cortex which was pre-incubated with [3H] -5-HT. This release is similar to that caused by nerve stimulation, that is, exocytotic release from the serotonergic nerve terminals, depending on the presence of Ca2 + in the medium of incubation. The release of 5-HT is regulated at the level of nerve terminals by autoreceptors, in Guinea pigs (as in humans) they belong to the subtype of h5-HT? B receptors. In this way, the agonists of the h5-HT? B receptors reduce the amount of [3 H] -5-HT released by electrical field stimulation while the release is increased by antagonists of this type of receptors. The tests to the compounds with this method are according to a convenient screen technique to determine the potency and functional effect of the new antagonists and agonists of the h5-HT? B receptors.

Methods and Materials Composition of the Shock absorber (mM) NaHC03 (25), NaH2P04.H20 (1.2), NaCl (117), KC1 (6), MgS04X7H20 (1.2), CaC12 (1.3), EDTA Na2 (0-03), the buffer is gasified for at least 30 min before use. The pH of the buffer is around 7.2 at room temperature but increases to about 7.4 to 3.7 ° C.

Preparation of the occipital cortex cuts Guinea pigs (200-250 g) were decapitated and the whole brain was removed. The occipital cortex was dissected and cut into 0.4x4 mm slices with a Mcllwain cutting machine. The white part of the tissue should be removed carefully with tongs before slicing it. The slices were incubated in 5 ml of buffer in the presence of 5 mM pargyline chloride. After incubation with 0.1 mM [3 H] -5HT for another 30 min the slices were transferred to a test tube and washed three times with the same volume of buffer. The slices were transferred to the superfusion chamber with a plastic pipette and were washed for 40 min with the buffer in the presence of a 2.5 μM citalopram inhibitor retainer with a flow of 0.5 ml / min.

Electrical stimulation of 5-HT release The superfused cushion was collected in 2 ml / fraction. The slices were stimulated by electricity with a sequence of pulses of frequency of 3 Hz, duration 2 ms and current 30 mA for 3 min at the 4th and 13th fractions. The tested drugs were added from the 8th fraction at the end of the experiments.

Results A first electrical stimulation (or k +) resulted in a standard amount of [3H] 5-HT released (Si). Between the first and second stimulation h5-HT? B is added to the medium whose results in a dose depend on the increase of the release (S2) after the second stimulation. See Fig.l.

The relationship between S2 / S? which is the percent release of [3H] -5-HT in the second stimulation (S2) divided by that of the first stimulation (Si) was used to estimate the effects of the drug in the release of transmitters.

Claims (2)

1. CLAIMS 1. A compound of general formula I fl) characterized because X is N or CH: Y is NR2CH2, CH2NR2, NR2-CO, CO-NR2 or NR2S02 characterized in that, R2 is H or C6-C6 alkyl; Ri is H, Ci-Ce alkyl or C3-C6 cycloalkyl; R3 is C1-Ce alkyl, C3-C6 cycloalkyl or (CH2) n-aryl, wherein the aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono or di-substituted with R 4 and / or R 5; characterized in that R4 is H, C? -C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C-C alkoxide, NR6R7, OCF3, S03CH3, S03CF3, S02NR6R7, phenyl, phenyl-Ci-Ce alkyl, phenoxide , Ci-Cβ alkylphenyl, an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O, S, SO and S02 characterized in that the substituent (s) is (are) selected from alkyl C? -C6, C3-C6 cycloalkyl and phenyl-C? -C6 alkyl; or COR8; characterized in that, R6 is H, C1-C3 alkyl or C3-C6 cycloalkyl; R7 is H, C? -C6 alkyl or C3-C6 cycloalkyl; and Rs is C? -C6 alkyl, C3-C6 cycloalkyl, CF3, NR6R7 phenyl or a heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO and S02; wherein wherein R5 is H, OH, CF3, 0CF3, halogen, C? -C6 alkyl or Ci-C? alkoxide; n is 0-4; R 9 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OCF 3, 0 CH 2 F, halogen, CONR 6 R 7, CN, CF 3, OH, C 1 -C 6 alkoxide, NR 6 R 7, S 0 3 CH 3, S 0 3 CF 3, S 0 2 NR 6 R 7, a substituted or unsubstituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and 0, characterized in that, the substituent (s) is (are) C? -C6 alkyl; or CORs; characterized in that R6, R7 and R8 are as defined above, as (R) -enantiomers, (S) -enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or a solvate thereof. 2. A compound according to claim 1 caracered because Y is NR2C0 or C0NR2. 3. A compost according to any of claims 1-2, characterized in that X is N. A compound according to any of claims 1-3 characterized in that Rx is H or C? -C6 alkyl. A compound according to any of claims 1-4 characterized in that R3 is (CH2) n-aryl. A compound according to any of Claims 1-4 characterized in that R3 is (CH2) n-aryl which is substituted with R4, which is an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, 0 and S, or C0R8. A compound according to any of claims 5 and 6 characterized in that n is 0 A compound according to claim 6 characterized in that R8 is R6R7 or a heterocyclic ring containing two heteroatoms selected from N and 0. A compound according to to any of claims 1-8 wherein Rg is C? -C6 alkyl, 0CHF2 halogen or C? -C6 alkoxide. A compound according to any of Claims 1-9 caracetrixzado because X is N, Y is NR2C0 and Rg is C6-C6 alkoxide 1. A compound according to claim 10 caracered because X is N, Yes NR2C0, R4 is morpholino or C0R8 and R9 is Ci-Cß alkoxide.
2. 2. A compound according to claims 1-9 characterized in that X is N, Y is NR2CO and R9 is Ci-Ce alkyl 13. A compound according to claim 12 characterized in that X is N, Y is NR2C0, R4 is morpholino or COR8 and Rg is C6-C6 alkyl. 14. A compound according to any of claims 1-9 characterized in that X is N, Y is CONR2 and Rg is C6-C6 alkoxide 15. A compound according to claim 14 characterized by X is N, Y is CONR2, R4 is morpholino or COR8 and Rg is Ci-Ce alkoxide 16. A compound according to any of claims 1-9 characterized in that X is N, and is CONR2 and R9 is Ci-Ce- 17. A compound according to claim 16 characterized in that X is N, Y is CONR2, R4 is morpholino or COR8 and Rg is C? -C6 alkyl 18. A compound that is (S) -N- [8-Methyl-5- (4-methyl-piperazin-1-yl) -3, -dihydro-2H-l-benzopyran-3-yl] -4- (dimethylaminocarbonyl) benzamide or N- (4-morpholinophenyl) -8-methoxy-5- (4-methylpiperazin-1-yl) -3,4-dihydro -2H-1-benzopyran-3-carboxamide, in the form of a free base or a pharmaceutically acceptable salt or a solvate thereof. A pharmaceutical formulation characterized in that as active ingredient a therapeutically effective amount of the compound of claims 1-18 as an enantiomer or racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof opcionally in association with diluents, excipients or carriers Inerts A pharmaceutical formulation according to claim 19 for use in the treatment of disorders mediated by 5-hydroxytryptamine A pharmaceutical formulation according to any of claims 19 or 20 for use in the treatment of mood disorders, disorders of anxiety, personality disorders, obesity, anorexia, bulimia, premestrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficits, hyperactivity disorders, migraine, memory disorders, pathological aggression, schizophrenia, disorders endocrine, attacks, dyskinesia, disease of Parkinson's, thermoregulatory disorders, pain, hypertension, urinary incontinence or vasospasm; or for control of tumor growth. 22. A compound as defined in any of claims 1-18 for use in therapy. 23. A compound as defined in claim 22 for use in the treatment of disorders in the central nervous system. 24. A compound as defined in claim 23 for use in the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premestrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, deficits in attention, disorders of hyperactivity, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, attacks, dyskinesia, Parkinson's, thermoregulatory disorders, pain or hypertension. 5. A compound as defined in claim 22 for use in the treatment of urinary incontinence or vasospasm or for the control of tumor growth. 6. A compound as defined in claim 22 for use in the treatment of disorders mediated by 5-hydroxytryptamine. 27. A compound as defined in claim 26 for its use as an antagonist of h5-HT? B. 28. The use of a compound defined in any of claims 1-18 in the manufacture of a medicament for the treatment of disorders in the central nervous system and / or urinary incontinence, vasospasm or for the control of growth of tumors. 29. The use according to claim 28 in the manufacture of a medicament for the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premestrual syndrome, sexual disturbances, alcoholism, abuse of the tobacco, autism, deficiencies in attention, disorders of hyperactivity, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, attacks, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension. 30. The use of a compound defined in any of claims 1-18 in the manufacture of a medicament for the treatment of disorders mediated by 5-hydroxytryptamine. 31. The use according to claim 30 characterized in that the compound according to any of claims 1-18 is used as an antagonist of h5-HT? B. 32. A method for the treatment of disorders in the central nervous system and / or urinary incontinence, vasospasm or tumor growth control by administration to a mammal including the human in need of such treatment of a therapeutically effective amount of a compound defined in any of claims 1-18. 33. A method according to claim 32 for the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, deficiencies in attention, disorders of hyperactivity, migraine, disorders of memory, pathological aggression, schizophrenia, endocrine disorders, attacks, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension. 34. A method for the treatment of disorders mediated by 5-hydroxytryptamine by administration to a mammal including man in need of such treatment of a therapeutically effective amount of a compound defined in any of claims 1-18. 35. A method according to claim 34 characterized in that the compound according to any of claims 1-18 is used as an anti- gonist of h5-HT? B. 36. A process for the preparation of the compound of formula I according to claim 1, characterized in that it includes. Ai) acylation, in the case where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, Y is NR2CO, R2 is hydrogen and, R3 and R9 are as defined in general formula I above, of a compound of formula A (A) (I) With an activated carboxylic acid R3-C0Lg? where Lgi is a leaving group or mediates the use of a carboxylic acid R3-COOH with an activating reagent. A (ii) Acylation in the case where Ri is C? -C6 alkyl, Y is NR2CO, R2 is C? -C6 alkyl, and X, R3 and R9 are as defined in general formula I above, of a compound of formula B , With an activated carboxylic acid R3-C0Lg? where Lgx is a saline group or by the use of a carboxylic acid R3-COOH with an activating reagent; A (iii) Acylation, in the case where Ri and R2 are hydrogen, Y is NR2C0, Rd is a protecting group and X, R3 and R9 are as defined in general formula I above, for a compound of formula C With an activated carboxylic acid R3-COLg? where Lgi is a leaving group or by the use of a carboxylic acid R3-COOH with an activating reagent, followed by removal of the protecting group Rd. (C) (I) B (i) The reaction in the case where Y is CONR2, R2, R3 and R9 are as defined in general formula I above, a Compound with a compound of formula XI wherein Lg is a leaving group; B (ii): The reaction in the case where Y is CONR2, R is H, R2, R3 and Rg are as defined in general formula I above with (D) (I) the exception of when R4 and Rg are substituents that are susceptible to undergo catalytic hydrogenation known to a person skilled in the art, a compound of formula D with a compound of formula XLI wherein Lg is a leaving group; C (i): The reaction in the case where Y is NR2S02, R2 is hydrogen, Ri, R3 and R9 are as defined in general formula I above, of a compound of formula E (E) (I) With an appropriate sulfonic acid activated R3S02Lg ?, where Lgi is a leaving group C (ii): The reaction, in the case where y is NR2S02, R2 is Ci-Cß alkyl, Ri, R3 and Rg are as defined in general formula I above, of a compound of formula E R. (With an appropriate sulfonic acid activated R3S02Lg ?, where Lgi is a leaving group; D: The reduction, where Y is NR2CH2 or CH2NR2, and X, Ri, R2, R3 and R9 are as in formula I above with the exception of when R4 and Rg are substituents that are susceptible to reducing reagents known to a skilled person. in the phoenix, of a compound of formula I above where Y is NR2CO or CONR2, and X, R1 f R2, R3 and R9 are as in formula I above, ( by an appropriate reducing agent; or Method E: The alkylation, in the case where Ri is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and is NR 2 CH 2 and X, R 2, R 3 and 9 are as defined in general formula I above with the exception of when R 4 and Rg are substituents that are susceptible to certain alkylations known to a person skilled in the art, of a compound of formula B (B) (I) 37. A compound that has the formula characterized because X is N or CH: Ri is C? -C6 alkyl or C3_C6 cycloalkyl; R2 is hydrogen or Ci-Cß alkyl; Y Rg is H, C? -Ce alkyl, C3-C? Cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, dr C? -C6 alkoxide, C? -C6-alkoxy-C? -C6 alkyl, NR6R7, S03CH3, S03CF3, S02NR6R7, a substituted or unsubstituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and 0, sn where the substituent (S) is (are) C? -C6; or C0R8; where, is H, Ci-Cß alkyl or cycloalkyl C3-C6; R7 is Ci-Cß alkyl or C3-Cß cycloalkyl; and R 8 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3, NR 6 R 7, phenyl or a heterocyclic ring containing one or two heteroatoms selected from N, 0 and S or a heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO and S02 where R6 and R7 are as defined above. 38. A compound that thongs the formula characterized in that, X is N; Rg is Ci-Cß alkyl, C3-C6 cycloalkyl, 0CF3, 0CHF2, OCH2F, halogen, CN, CF3, OH, C?-C6 alkoxide, C alco-C6 alkoxy-C?-C6 alkyl, NR6R7, S03CF3, S02NR6R7, a substituted or unsubstituted heterocyclic or heteroaromatic ring containing one or two hetroatoms selected from N and 0, characterized in that the substituent (s) is (are) Ci-Cß alkyl; or C0R8; characterized in that, Re is H, C? -C6 alkyl or C3-Ce cycloalkyl; R7 is H, C2-Ce alkyl or C3-Ce cycloalkyl; R 8 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, CF 3, NR 6 R 7, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, 0 and S or a heterocyclic ring containing one or two heteroatoms selected from from N, 0, S, SO and S02 characterized in that R6 and R7 are as defined above; and R is a protecting group. 39. a compound that has the formula characterized in that, Y is CONR2; characterized in that R 2 is hydrogen or C 1 -C 6 alkyl; R3 is C6-C6 alkyl, C3-C6 cycloalkyl or (CH2) n-aryl, characterized in that the aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, 0 and S and that can be be mono- or di-substituted with R4 and / or Rs; characterized in that R4 is H, C? -Ce alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C? -C6 alkoxide, NR6R7, 0CF3, S03CH3, S03CF3, S02NR6R7, phenyl, phenyl-C? -C6 alkyl, phenoxido, C6-C6 alkylphenyl, an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O, S, SO and S02 characterized in that the substituent (s) is (are) selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and phenyl C 1 -C 6 alkyl; or COR8; characterized in that R6 is H, C? -C6 alkyl or C3-C6 cycloalkyl; and R8 is C? -C6 alkyl, C3-C6 cycloalkyl, CF3, NR6R7, phenyl, or a heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO, and S02; characterized in that R5 is H, OH, CF3, 0CF3, halogen, C6-C6 alkoxy alkyl; n is 0-4; and Rg is Ci-C6 alkyl, C3-C6 cycloalkyl, 0CF3, 0CHF2, 0CH2F, halogen, CONR6R7, CN, CF3, OH, C? -C6 alkoxide, NR6R7, S03CH3, SO3CF3, S02NR6R7, a heterocyclic ring or substituted or unsubstituted heteroaromatic containing one or two heteroatoms selected from N and 0, characterized in that the substituent (s) is (are) C? -C6 alkyl; or C0R8; characterized in that Rß, 7 and Rs are as defined above. DERIVATIVES SUBSTITUTED FROM CHROMINE SUMMARY OF THE INVENTION The present invention relates to novel piperidinyl or piperazinyl substituted derivatives - 3,4-dihydro-2H-a-benzopyran, having the formula (1) wherein X is N or CH is; And it is NR2 CH2 CHX NRX; NR2 C? ", CONR2 or NRX S0, wherein aryl is phenyl a heteroamate ring containing one or two heteroatoms selected from N.O and S and which may be mono or bisubstituted, n ex 0-4, R2 is alkyl C1-C6 C3-C6 cycloalkyl OCF3 OCHF2 OCH2F halogen, CONR6R7 CN, CF3 OH a heteroaromatic or substituted or unsubstituted heteroatom ring containing one or two heteroatoms selected from N.