MXPA00002770A - Substituted chroman derivatives - Google Patents

Abstract

The present invention relates to new piperidyl- or piperazinyl-substituted dihydro-2H-1-benzopyran derivatives compounds having formula (I) wherein X is N or CH;Y is NR2CH2, CH2NR2, NR2CO, CONR2, NR2SO2 or NR2CONR2 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 with R4 and/or R5;and n is 0-4;as (R)-enantiomers, (S)-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds.

Description

SUSPECTED DERIVATIVES OF C-ROMAN Field of the invention The present invention relates to a new derivative of dihydro-2H-1-benzopyran substituted with piperidyl or piperizinyl as enantiomers- (R), enantiomers- (S) or racemates in free base form or pharmaceutically acceptable salts or solvates thereof, a process for its preparation, pharmaceutical compositions containing said active compound therapeutically and to the use of said active compound in therapy.

An object of the invention is to provide a compound for use in therapy, especially a compound having a selective effect on the subgroup of 5-hydroxytryptamine receptors, designated the -5-HT1B receptor (previously called the 'receptor-5'). HT; _μ) in mammals including man.

It is also an object of the invention to provide a compound with a therapeutic effect subsequent to oral administration.

REF .: 33003 Background of the invention Several disorders of the central nervous system such as depression, anxiety, etc. They seem to affect the alteration of the noradrenaline of neurotransmitters (NA) and 5-hydroxytryptamine (5-HT), the latter also known as serotonma. The drugs most commonly used in the treatment of depression are believed to act to improve the neurotransmission of either or both of these physiological agonists. It seems that the increase in 5-HT neurotransmission primarily affects the state of depressed mood and anxiety, while the increase in noradrenaline neurotransmission affects the delay of symptoms that appear in depressive patients. The invention relates to compounds which have an effect on the neurotransmission of 5-HT.

It is believed that the activity of serotonin, or 5-HT, is involved in several different types of psychic disorders. For example, it is believed that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has also been implicated in various conditions such as eating disorders, gastrointestinal disorders, and disorders of vascular regulation and sexual disturbances.

The 5-HT Receptors Various effects of 5-HT may be related to the fact that serotonergic neurons stimulate the secretion of various hormones, e.g. cortisone, prolactin, ß-endorphin, vasopressin and others. The secretion of each of these and other hormones appears to be regulated on a specific basis by several different 5-HT receptor subtypes Serotomna) With the help of a molecular biological technique, up to now these receptors have been classified as 5-HT, 5-HT, 5-HT, 5-HT-, 5-HT-, 5-HT, 5-HT. -, with the 5-HT receptor; further divided into the 5-HTiA subtypes, -HT - .., 5-HT: _, 5-HT ::, 5-HT- .. and 5-HT -... Each of the receptor subtypes is involved in a different function of serotonin and It has different properties.

Regulation of 5-HT transmission The release of 5-HT is a regulated feedback of two different subtypes of 5-HT receptors. 5-HTü autoreceptors Inhibitors are located in the bodies of cells in the suture of the nucleus which under stimulation of 5-HT decreases the propagation of the impulse in the 5-HT neurons and for that reason reduces the release of 5-HT in the nerve terminals. Another subtype of inhibitory 5-HT receptors is located at the 5-HT nerve terminals, the h5-HT1B receptors (in the rodent r5-HT receptors) which regulated the synaptic concentration of 5-HT by controlling the amount of 5-HT released . In addition, an antagonist of these terminal autoreceptors increases the amount of 5-HT liberated by nerve impulses which can be shown in both experiments vi vi and in vi vo.

The use of a h5-HT: _ terminal autoreceptor antagonist could consequently increase the 5-HT smaptic concentration and increase the transmission in the 5-HT system. So this could produce an antidepressant effect making it useful as a medication for depression.

There are also other locations of the 5-HT_B receptor subtype. A large portion of these postsynaptic receptors appear to be located in the nerve terminals of other neuronal systems (so-called heteroreceptors). Since the h5-HT: B receptor mediates inhibitory responses, an antagonist of this receptor subtype can also increase the release of other 5-HT neurotransmitters.

Compounds having h5-HTiB activity can be divided according to how well they are known and recognized in pharmacological tests towards full agonists, partial agonists and antagonists.

Description of the invention The object of the present invention is to provide a compound having a selective effect on the h5-HT? B receptor, preferably with antagonistic properties, as well as having a good bioavailability. The effect on other receptors selected from, for example, the 5-HT-, -, 5-HT_A, D, Oz ~, D, a and a_ receptors have been investigated.

Accordingly, the present invention provides the compounds of the formula I (i) Where X is N or CH Y is NR: CH :, CH; -NR-, NR.CO, CO-NR_, NR2SO :. or NR-CONR; Where Rr is H or C- alkyl. -C., Or C.-C. cycloalkyl. R; is C -C alkyl. , C-C cycloalkyl, or (CH -) - aryl Where the aryl is phenyl or an aromatic ring containing one or two heteroatoms selected from NO and S which may be mono- or di-substituted with R- and / or R5; Where R4. is H, C3-C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, d-Cß alkoxy, NRÓRT, OCF3 S03CH3, S03CF3, S02NR6R7, phenyl, phenyl-C-alkyl, phenoxy, alkylphenyl C: - C6, an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO, and SO: wherein the substituent (s) is (are) selected from C?-C6 alkyl, C-cycloalkyl; phenyl-C? -C6 alkyl, (CH2), tORc wherein m is 2-6 and R_ is H, C-C0 alkyl, C-C6 cycloalkyl or phenyl-C: -C_ alkyl, and CORe, an aromatic ring optionally substituted contains one or two heteroatoms selected from N, 0 and S wherein the substituent (s) is (are) selected from C-C-alkyl, C-C-cycloalkyl, and phenyl-C-C-alkyl. , or COR-; Where R. is H, C -C alkyl or C3-C_ cycloalkyl; R is H, C -C alkyl or C_C cycloalkyl; and R8 is C-C alkyl, C-C3 cycloalkyl, CF3, NR6R, phenyl, a heteroaromatic ring contains one or two heteroatoms selected from N, 0, and S, or a heterocyclic ring contains one or two heteroatoms selected from N, O, S, SO and SO_; R5 is H, OH, CF3, OCF3, halogen, C: -C6 alkyl or alkoxy; And n is 0-4; As enantiomers- (R), enantiomers- (S) or a racemate in the form of a free base or a pharmaceutically acceptable salt or a solvate thereof which possess a high selective effect on the h5-HT? B receptor and also show Sufficient bioavailability after oral administration.

In the present context he alkyl C-C. It can be straight or branched. He rented C -C-. it can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or Hexyl.

In the present context the C.-C. It can be straight or branched. The C -C alkoxy can be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy , n-hexyloxy or i-pentyloxy.

In the present context, the cycloalkyl C; - C6 can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclohexyl.

In the present context, halogen can be fluorine, chlorine, bromine or iodine.

In the present context, the athetero heteroatom ring contains one or two heteroatoms selected from N, 0 and S preferably is a 5-or 6- membered heteroaromatic ring and may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazyl, pyrazolyl, pyridazmyl, pyridyl, pyridimidyl, pyrrolyl, thiazolyl or thienyl. Any aromatic ring can be replaced or not replaced.

In the present context the aromatic ring contains one or two heteroatoms selected from N, O, S, SO, and SO may optionally contain a carbonyl function, and is preferably an integrated heterocyclic ring of 5-, 6-7 7- membered and can be ylidazolidinyl, ylidazolyl, morpholyl, piperazyl, pipepdyl, piperidyl, pyrazolidyl, pyrrolidimyl, pyrrolmyl, tetradipyranyl, thiomorpholinyl, preferably piperidino, 1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.

A preferred embodiment of the invention relates to the compound of formula I wherein Y is NHCO or CONH i.e. amides. Of these compounds, the compounds wherein R3 is unsubstituted phenyl or mono- or di-substituted phenyl and especially ortho-, meta- or para-substituted phenyl, and particularly those wherein the R- substituent is phenyl, phenyl-C-alkyl : -C6, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF3, 4-piperidon-1-yl, n-butoxy, or CORI wherein RB is phenyl, cyclohexyl, 4-piperidon-l-yl, piperazinyl, morpholmo, CF3, piperidino or NR6Rt, are preferred.

Examples of combinations of substituents are: X is N, Y is CONR., R. is H, CH., C-H, or CH-, R: is H, R. is (CH.) _-Phenyl, R - is piperidm, R- is H; X is N, Y is NR_CO, R: is H, CH. ,, C_Hr or C3H R_ is H, R 3 is (CH.); -fen? Lo, R. is phenyl, phenylmethyl or phenylethyl, R is H; X is N, Y is NR CO, R is H, CH_, C: H or C.H-, R: is H, R; is phenyl, R; is piperidino, R is H; X is N, Y is CONR2, R_ is H, CH3, C2H5 or C3H7, R_ is H, Rs is phenyl, R4 is hydroxyethyl-piperazinyl, R5 is H; X is CH, Y is CONR2, Ri is H, CH3, C2H5 or C3H, R2 is H, R3 is CH_-phenyl, R is phenyl, phenylmethyl or phenylethyl, R. is H; X is CH, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R_ is H, R- is phenyl, R- is piperidino, R5 is H; X is N, Y is NR_CO, R: is H, C2H5 or C3H7, R_ is H, R3 is (CH;) - phenyl; X is CH, Y is CONR_, R: is H, C_H5 or C3H-, R_ is H, R3 is CH_-phenyl; X is N, Y is NR2CO, R: is H, CH3, C: H5 or C3H, R? is H, R- is CH-phenyl, R is phenyl, phenylmethyl or phenylethyl, R is H; X is CH, Y is NR.CO, R: is H, CH-, C.H * or C-, H-, R_ is H, R-. is phenyl, R; is morpholino, R. is H; X is CH, Y is CONR_, R. is H, CH_, C: H. or C-.H-, R; is H, R. is phenyl, R- is morpholino, R- is H; X is CH, Y is CONR, R- is H, CU., C-H = or C-, H-, R- is H, R_ is phenyl, R is pipepdino, R- is H; X is N, Y is CONR., R is H, CH., C: H < or CH-, R_ is H R is CH-phenyl, R- is morpholmo, R is H; X is N, Y is NR-CO, R is H, CH.-, C_H, or C..H-, R. is H, R% is CH-phenyl, R4 is morpholino, R ^ is H; X is CH, Y is NR2CO, R_ is H, CH3, C2H5 or C3H7, R_ is H, R3 is (CH2); -phenyl, R4 is piperidino, R £ is H; X is N, Y is NR2CO, Ri is H, CH3, C2H5 or C3H7, R? is H, R3 is phenyl, R. is hydroxyethyl, R5 is H; X is CH, Y is CONR;, R: is H, CH3, C2H5 or C3H-, R_ is H, R3 is phenyl; X is NH, Y is CONR;, Ri is H, CH3, CH5 or C3H-, R? is H, R3 is phenyl, R ^ is morpholino, R5 is H; X is N, Y is CONR2, R_ is H, CH3, C, H5 or C3H7, R_ is H, R5 is phenyl, Rj is piperidino, Rs is H; X is N, Y is NR_CO, Ri is H, CH3, C2H5 or CH-, R2 is H, R3 is phenyl, R- is benzyloxyethyl-piperazinyl, R6 is H; X is CH, Y is NR.CO, R. is H, CH3, C: H * or C3H7, R: is H, R3 is (CH;) - phenyl; X is CH, Y is NR-CO, R. is H, C? E-. or C5H7, R? is H, R. is phenyl, R is phenyl, phenylmethyl or phenylethyl, R = is H; X is N, Y is CONR, R is H, CH ,, C: H. or C-, H7, R2 is (CH-); -phenyl; X is N, Y is CONR, R is H, CH, C H- or C-.H-, R: is H, R is CH-phenol, R is piperidino, R. is H; X is N, Y is NRCO, R- is H, CH ,, C_H, or CH-, R_ is (CH;), -phenyl, R_ is pipendmo, R = _ is H; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R; is H, R3 is phenyl, R is phenyl, phenylmethyl, phenylethyl, R5 is H; X is N, Y is NR, CO, R_ is H, CH3, C, H5 or C3H-, R; is H, R3 is phenyl, R is morpholino, Rs is H; X is CH, Y is CONR;, R_ is H, CH3, C_H_. C..H-, R2 is H, R-; is CH; -phenyl, R is piperidino, Rs is H; X is N, Y is CONR;, R: is H; CH3, C2H5 or C3H, R? is H, R3 is CH;-phenyl; X is N, Y is CONR;, Rx is H, CH3, C2Hb or C3H7, R; is H, R :. is (CH;): -phenyl, Ri is morpholino, R5 is H; X is N, Y is CONR;, R: is H, C; H5 or C3H-, R_ is H, R? is phenyl, R4 is benzyloxyethylene-piperazinyl, R5 is H; X is N, Y is CONR ^, R: is H, CH3, C, Hf or C3H7, R; is H, R- is phenyl, R: is CORs, R- is morpholino; X is CH, Y is NR CO, R: is H, CH: ,, C; H. or C3H-, R is H, R-. is CH3-phenyl, R; is phenyl, phenylmethyl or phenylethyl, R = is H; X is CH, Y is NR ^ CO, R; is H, CH3 C, H5 or C3H-, R; is H, R-. is (CH); - phenyl, R. is morpholino, Rs is H, X is N, Y is CONR, R: is H, CU -, C; H- or C_H7, R2 is H, R-. is (CH_); -phenyl, R is phenyl, phenylmethyl or phenylethyl, R is H; X is N, Y is NR2CO, R_ is H, CH3, C2H5 or C3H7, R; is H, R3 is phenyl, R is phenyl, phenylmethyl or phenylethyl, Rs is H; X is CH, Y is NR, CO, R_ is H, CH3, C, H5 or C3H-, R: is H, R3 is CH: -phenyl, R4 is piperidino, R5 is H, X is CH, and is NR; CO, R_ is H, CH3, CH3 or C3H-, R_ is H, R3 is CH: -phenyl, R is COR8, Re is NR6R7, R6R7Ch3, C; H5 or C3H7; X is CH, Y is CONR;, R_ is H, CH3, C; H5 or C3H7, R; is H, R3 is phenyl, R is phenyl, phenylmethyl or phenylethyl, Rs is H; X is CH, Y is CONR;, R: is H, CH3, C; H5 or C3H-, P_ is H, R-. is (CHb: -fyl, R is morphol, R * is H, X is CH, Y is NR.-CO, R-. is H, CH3, CH, or CH-., R is H, R :. is (CH;), -femlo; X is CH, Y is NR CO, R is H, CH3, C: H or C-, H-, R_ is H, R is (CHJ -phenyl, R, is phenyl, phenylmethyl or phenylethyl, R- is H; X is CH, Y is NR CO, R is H, CH., C_H- or C-, H-, R is H, R3 is CH: -fen, R, is morphol, R is H, X is CH, Y is NR CO, R is H, CH3, C, H or CH-, R, is H, R3 is phenyl, R is COR, R is morphol; is CH, Y is CONR, is H, CH., CH, or CH, R, is H, R3 is (CH;); -phenyl; X is CH, Y is CONR2, R_ is H, CH3, C2H5 or C3H-, R; is H, R3 is (CH2) 2-fyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H; X is CH, Y is CONR;, R_ is H, CH3, C: H £ or C3H7, R; is H, R3 is CH; is phenyl, R is morpholino, R5 is H; X is CH, Y is CONR2, Rx is H, CH3, C, Hs or C3H7, R- is H, R3 is phenyl, R4 is piperazinyl, R5 is H; X is CH, Y is NR2CO, NR, CO, Ri is H, CH3, C, H5 or C H7, R; is H, R3 is phenyl; X is CH, Y is NR, CO, R_ is H, CH3, C, H5 or C3H7, R_ is H, R3 is phenyl; X is N, Y is NR, CO, R: is H, CH3, C, H5 or C3H7, R; is H, R3 is CH; -phenyl, R is piperidino, R is H; X is N, Y is COR;, R: is H, CH3, C; H or C3H- > , R? is H, R3 is CH2-phenyl, R is phenyl, phenylmethyl or phenylethyl, R_ is H; X is N, Y is CONR, R is H, CH., C-H. or C3H-, R-is H, R-. is (CH :); -phenyl, R4 is pipepdino, Rs is H; X is N, Y is NR CO, R. is H, CH ,, CH. or C3H7, R2 is H, R3 is (CH2); -phenyl, R, is morpholmo, Rs is H; X is N, Y is NR CO, R is H, CH., CH, or CH, R2 is H, R-. is phenyl, R4 is piperazimyl, R- is H, X is N, Y is CONR., R is H, CH_, CH- or C.H-, R2 is H, R3 is phenyl, R is piperazyl, Rs is H; X is N, Y is CONR2, R_ is H, CH3, C2H5 or C3H-, R_s H, R2 is phenyl, R4 is COR3, Re is cyclohexyl; X is N, Y is CONR2, Ri is H, CH3, C2H5 or C3H7, R; s H, R 3 is phenyl; X is N, Y is NR2CO, R_ is H, CH3, C2H5 or C3H-, R_s H, R3 is CH; The preferred compounds are: (S) -N- [5- (4-methylpiperazin-1-yl) -3, -dihydro-Hl-benzopyran-3-yl] -4-morpholinobenzamide (S) -N- [5- (4-methylpiperazin- 1-yl) -3, -dihydro-Hl-benzopyran-3-yl] -4-piperidinobenzamide (S) -N- [5- (4-methylpiperazin-1-yl) -3, -dihydro-Hl-benzopyran- 3-yl] -4-b-toxibenzamide (S) -N- [5- (-methylpiperazin-1-yl) -3,4-dihydro-Hl-benzopyran-3-yl] -4-trifluoromethylbenzamide (S) -N - [5- (4-methylp? Perazin-l-yl) -3, -dihydro-Hl-benzopyran-3-yl] -4-N, N-diethylaminobenzamide (S) -N- [5- (4-methylpiperazine -1-yl) -3,4-dihydro-Hl-benzopyran-3-yl] -4-trifluoromethoxybenzamide (S) -N- [5- (4-methylpiperazin-1-yl) -3, -dihydro-Hl- benzopyran-3-yl] -4- (4-piperidon-l-yl) benzamide (S) -N- [5- (4-methyl-piperazin-1-yl) -3, -dihydro-2H-l-benzopyran-3 -yl] -4- (hexahydro-1, -diazepin-5-on-1-yl) benzamide and (S) -N- [5- (4-methylpiperazin-1-yl) -3, -dihydro-2H- l-benzopyran-3-yl] -4- (4-benzylpiperazin-1-yl) benzamide The compounds of the present invention are in the form of the racemate or the (R) - or (S) - enantiomer in the free base or pharmaceutically acceptable salt form or solvate thereof. Compounds in the form of the (S) -enantiomer are preferred.

Both organic and inorganic acids can be used to form. salts of pharmaceutically acceptable non-toxic acids of the compounds of the invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromihydric, citric, acetic, lactic, tartaric, dibenzoyltartaric, diacetyltartaric, palmoic acids, ethanedisulfonic, sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3-dihydroxybenzoic, 3,5-dihydroxybenzoic, 3-hydroxy- 2-naphthoic, nicotonic, methanesulfonic, ethanesulfonic, idroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulphanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfanic, fumaric, maleic, and benzoic. These salts are easily prepared by methods known to a person skilled in the art.

Preferred solvates of the compound of this invention are hydrates.

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

According to the present invention the compound of the invention should normally be administered orally, straight or by injection, in the form of pharmaceutical formulations comprising both the active ingredient as a free base or a non-toxic, pharmaceutically acceptable acid addition salt. , eg The hydrochloride, bromohydrate, lactate, acetate, phosphate, sulfate, sultanate, citrate, tartrate, oxalate, and the like format in a pharmaceutically acceptable dose. The dose format can be a solid, semi-solid, or a liquid preparation. Usually the active substance should constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for desired preparations for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.

In producing pharmaceutical formulations containing the compound of the invention in the unit dose format for oral application, the selected compound can be mixed with a solid excipient, e.g. lactose, sucrose, sorbitil, mannitil, starches such as potato starch, corn starch, or amyl pectin, cellulose derivatives, a coating such as gelatin or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate , polyethylene glycol, waxes, paraffins, and the like, and also compressed inside the tablet. If the coated tablets are required, the center, prepared as previously described, can be coated with a solution concentrated in sugar which can contain, e.g. Gum arabic, gelatin, talc, titanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to a person skilled in the art, dissolved in an easily volatile organic solvent or a mixture of organic solvents. The pigment can be added to these coatings to easily distinguish between tablets containing active substances or different amounts of the active compound.

• For the preparation of soft gelatine capsules, the active substance can be mixed with a vegetable oil or pol: -ethylene glycol e.g. Hard gelatin capsules may contain granules of active substances using both the excipients mentioned above for tablets, e.g. lactose, sucrose, sorbitol, mannitol, starches, (potato starch, corn starch, or amylopectin, e.g.), derivatives of cellulose or gelatin. Also liquid or semi-liquid from drug can be filled into capsules of hard gelatin The unit doses for the application of the rectum can be solutions or suspensions or they can be prepared in the format of suppositories comprising the active substance in a mixture with vegetable oil or paraffin oil. Liquid preparations for an 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 active substance described herein. The balance of the existing sugar in the mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, sucrose and carbaximethyl cellulose as a thickening agent or excipients known to a person skilled in the art.

Solutions for parenteral applications by injection can be prepared in an aqueous pharmaceutically acceptable salt solution of the active substance soluble in water, preferably in a concentration of about 0.1% to about 10% by weight. These solutions may also contain stabilizing agents and / or deactivating agents and may conveniently be supplied in several unit doses of ampoules.

An adequate daily dosage of the compound of the invention in the therapeutic treatment of humans are approximately 0.01-100 mg / kg of body weight in oral administration and 0.001-100 mg / kg in body weight in a parenteral administration.

The compound of the invention can be used in a combination with inhibitor of 5-HT inhibitory intake, such as fluoxetine, paroxetine, citalopram, clomipramine, sertraline, alaproclate, or fluovoxamma, preferably paroxetine or citalopram. Another possible combination is to use the compound of the invention together with a monoamine oxidase inhibitor, such as moclobemide, tranylcipramine, brofaromide or phenelzine, preferably moclobemine or phenelzine. Yet another possible combination is the compound of the invention together with a 5-HT? Antagonist. Such as the compounds described in WO 96/33710. Preferably (R) -5-carbamoyl-3- (N; N-d? C? Clobut? Lammo) -8-fluoro-3,4-dihydro-2H-l-benzopranol.

Medical and pharmaceutical use In a further aspect of the present invention provides the use of the formula I in therapy as an antagonist h5-HT_B, partial agonist or total agonist, preferably as an antagonist and the use in the treatment of disorders mediated by 5-hydroxytptamine. Examples of such disorders are disorders in the CNS such as disorders in the mood (depression, major depressive episodes, dysthymia, temporary affective disorder, depressive phases of bipolar disorders), anxiety disorders (obsessive-compulsive disorder, panic disorders with / without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, post-traumatic nervous tension disorder), personalized disorders (impulse control disorders, tpchotellomania), obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, poor attention, disordered hyperactivity (memory damage associated with age, presenile and senile dementia), pathological aggression, schizophrenia, endocrine disorders (eg hyperprolactmaemia), heart attack, disc disease, Parkinson's disease, thermoregulation, anxiety and hypertension . Other examples of disorder-mediating hydroxytrythoma are urinary incontinence, vasospasm, and tumor growth (e g lung carcinoma).

Preparation methods The present invention also relates to the process of preparing the compound of formula I. Along and throughout the follow-up of the description of such processes is included this, where corresponding, adequately protected groups must be added to, and subsequently removed of, the various reagents and intermediates in a manner such that they should be understood by an expert in the field of organic synthesis. A conventional procedure for the use of such protected groups as well as examples of suitably protected groups are described, for example, in "Protective Groups in Organic Synthesis" t: w: Greene, Wiley_interscience, New York, 1991. intermediates Intermediary preparation methods 1. In the case where Y is NR2CO and X is N (i) Benzylation of the compound of formula II, described in: Thorberg S-O .; may.; Akesson C; Svensson K .; Nilsson J.L.G. Acta pharm, Suec. 1987, 24 (4), 169-182 as a racemate or in patent application WO 93/07135 as an enantiomer, (II) To obtain a compound of formula III it can be carried out by a reaction with a suitable benzylating agent, e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol, e.g. benzyl mesylate or benzyl tosylate. The reaction can be carried out using a salt or the base of compound II in a suitable solvent, e.g. N, N-dimethylformamide, acetone or acetonitrile, with a suitable base, e.g. NaOH, NaHCO3, K, C03 or a trialkylamine such as triethylamine, at a temperature within the range of + 20 ° C to + 150 ° C. The presence of a suitable catalyst, e.g. Potassium iodide or sodium iodide can increase the reaction rate. iii) Demethylation of the compound of formula III (III) To obtain a compound of formula IV it can be carried out by treating the compound with an acid reagent such as HBr, Hl, HBr / CH3COOH, BBR_, A1C13, aqueous pyridine-HCl or with a basic nucleophilic reagent such as CH.CH "S ~ 0 C_H ~ S "in a suitable solvent Suitable solvents may be methylene chloride or chloroform and the reaction may occur between -78 ° C and + 60 ° C. (iii). The conversion of the compound of formula IV to the compound of formula V (IV) (V) It can be carried out by the reaction with a compound of formula VI (SAW).

Where Lg is an indicator of an absent group, e.g. a halogen, such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and R, and R are hydrogen or a lower alkyl group, e.g. a methyl. The process can be carried out with a salt of the compound of formula IV obtained by a reaction with a base such as KC03, Na2CO3, KOH, NaOH, BuLi or NaH. The reaction can be carried out in a suitable solvent, e.g. 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 reconfiguration of a compound of formula V to a compound of formula VII.

(V) (VII) It can be carried out in a suitable solvent, e.g. an aprotic solvent such as N.N-dimethylformamide, dioxane, 1, 1, 3, 3, -tetramethylurea, tetrahydrofuran or hexamethylphosphoric triamide, with a suitable base, e.g. K2C03, KCO, potassium tert-butoxide or NaH, at a temperature within the range of + 20 ° C to + 150 ° C. The presence of a cosolvent Such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyridone or hexamethylphosphoric triamide in an appropriate concentration in the solvent may increase the reaction rate. (v) The hydrolysis of a compound of formula VII to compound VIII can be carried out under acidic conditions using acids such as H 2 S0, HCl, or HBr, in a suitable solvent, e.g. H20, ethanol, methanol or mixtures thereof, and the reaction may occur between + 20 ° C and + 100 ° C or under basic conditions using bases such as NaOH or KOH in a suitable solvent, e.g. H; 0, ethanol, methanol, or mixtures thereof, and the reaction may occur between + 20 ° C and + 100 ° C. (vi) The conversion of the compound of formula VIII to the compound of formula IX (vm) (DO It can be carried out by a) reaction with a compound of formula X (X) Where R: is C? -C6 alkyl or C-C cycloalkyl. The process can be carried out in a suitable solvent, e.g. an aprotic / anhydrous solvent such as tetrahydrofuran N, 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, e.g. LiAlH4, in a suitable solvent, e.g. diethyl ether or tetrahydrofuran at a temperature between + 20 ° C and reflux, b) By a reaction with the compound of formula XI (XI) Where Lg is an indicator of an absent group, e.g. a halogen such as he, chloro, bromo or iodo or an alkane- or arenesulfonyloxy group such as the p-toluenesulfonyloxy group and R: is hydrogen, alkyl- or C3-C6 cycloalkyl. The process can be carried out in a suitable solvent such as ethanol, butanes, N, N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base, e.g. K; C03, NaHCO; or KOH, and the reaction can occur between + 20 ° C and + 150 ° C. (vii) The conversion of the compound of formula IX to the compound of formula XII (XII) Where R is C-C alkyl or C-C cycloalkyl it can be carried out by a) Hydrogenation using a catalyst containing palladium, platinum, rhodium, or nickel in a suitable solvent, e.g. acetic acid or ethanol, and at a reaction temperature between + 20 ° C and + 120 ° C, or b) The debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C and at the reaction temperature of + 20 ° C and reflux. (viii) the conversion of the compound of formula IX, where R. is hydrogen, to the compound of formula XIII (IX) (x) Where R. denotes a suitable protecting group, it can be carried out by a) Hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent, e.g. acetic acid or ethanol, at a reaction temperature between + 20 ° C and + 120 ° C and reflux. b) The debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C and reflux.

Said reaction is followed by the protection of the piperazino ring in a suitable solvent, e.g. Methyl chloride or chloroform, with an appropriate protective reagent e.g. di-tert-butyl dicarbonate with a suitable base, e.g. triethylamine or K; C03 and at a reaction temperature between -20 ° C and + 60 ° C, resulting in the compound of formula XIII. 2. In the case where Y is NR2CO and X is CH (i) The halogenation of the compound of formula XIV, either as a racemate (described in: Thorberg S-0, Hall H., Akesson K .; Svensson K .; Nilsson JLG Acta Pharm. Suec. 1987, 24 ( 4), 169-182), or as an enantiomer.

(XJV) (XV) To obtain a compound of formula XV it can be carried out by an electrophilic aromatic substitution using a suitable agent for halogenation such as Br., Cl_, I_, IC1, or S0: C1. The reaction can be carried out using the salt or the base of compound XIV in an appropriate solvent, e.g. acetic acid, HCl / ethanol or water, with or without a suitable base, e.g. an alkali metal acetate such as sodium acetate and a reaction temperature between -20 ° C and room temperature.

(XVI) (ii) Benzylation of the compound of formula XV, either as a racemate or as an enantiomer, obtaining a compound of the formula can be carried out by a reaction with a suitable agent for benzylation, e.g. benzyl halide such as benzyl bromide or benzyl chloride. The reaction can be carried out the salt or the base of compound XV in suitable solvent, e.g. N, N-dimethylformamide, acetone or acetonitrile, with a suitable base such as triethylamine NaOH, NaHCO. or K: CO-- at a temperature within the range of + 20 ° C to + 150 ° C The presence of a suitable catalyst, e.g. A metal halide alkali such as potassium iodide or sodium iodide, can increase the reaction rate.

(XVII) (iii) The conversion of the compound of the formula XVI to the compound of the formula XVII, wherein Ri is C ~ C alkyl or CC cycloalkyl-, can be carried out by a metal-halogen exchange, in a suitable anhydrous solvent such as tetrahydrofura or diethyl ether using a suitable alkyl lithium or metal, eg butyllithium, lithium or curved magnesium, followed by treatment with an appropriate piperidone such as N-methyl-4-piperidone and a subsequent suitable treatment. The reaction can be carried out at a temperature within the range of -78 ° C to room temperature. ixvpn (iv) The compound of formula XVII can be reduced to the compound of formula XVIII by a treatment with a suitable reducing agent such as sodium borohydride and a suitable protonated agent such as CF3COOH, CF3SO.H or HCOOH and a suitable solvent such as tetrahydrofuran or diethyl ether. The reaction can be carried out at a temperature between 0 ° C and (XIX) (v) The demethylation of the compound of formula XVIII to obtain a compound in formula XIX can be carried out by treating the compound with acid reagents such as aqueous HBr, Hl, HBr / acetic acid, BBr-, A1C13, pi'ridine- HCl or as a nucleophilic basic reactant such as CH-S "" or CH-.CH4S "in a suitable solvent Suitable solvents may be methylene, or chloroform and the reaction may occur between -78 ° C and + 60 ° C .

(XX) (vi) The conversion of the compound of the formula XIX to the compound of the formula XX can be carried out with a compound such as the anhydro trifluoromethanesulfonic acid in a suitable solvent such as the chloride or the carbon tetrachloride in the presence of a base such as 2, 4, 6, -colidine, triethylamine or piperidine at a reaction temperature within the range of -78 ° C and room temperature.

(XXJ) (vii) The conversion of the compound of formula XX to the compound of formula XXI can be carried out by a) hydrogenation using a catalyst such as palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature between + 20 ° C and + 120 ° C, or b) Reaction in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C and reflux. 3. In the case where Y is CONR2 and X is N (i) Nitration of the compound of formula XXII either as a racemate (described in: Thorberg S-0; May H; Akesson C; Svesson K.; Nilsson JLG Acta Pharm. Suec. 1987, 24 (4) , 169-182), or as an enantiomer to obtain a compound in formula XXIII, (xxp) (xxm) Where R_ is C-C alkyl, it can be carried out by an electrophilic aromatic substitution using a suitable nitrating reagent such as nitric acid or nitric acid and sulfuric acid in a suitable solvent, e.g. acetic acid, anhydrous acetic acid or water, at a temperature between -20 ° C and room temperature. (ii) Demethylation of the compound of formula XXIII to obtain a compound in formula XXIV (xxrv) It can be carried out by treating the compound with an aqueous acid reagent such as aqueous HBr, Hl, HBr / CH3COOH, BBr3, A1C13, pyridine-HCl or with a basic nucleophilic reagent such as CH- .CH.; S "" o CHsSb Suitable solvents can be methylene chloride or chloroform and the reaction can occur between -78 ° C and + 60 ° C, During the demethylation of XXIII, the hydrolysis of the esters can occur and the function of the acid can then be converted back to the ester by methods known to one skilled in the art. (see T: W: Greene, Wiley-Interscience, New York, 1991). (iii) The conversion of the compound of formula XXIV to the compound of formula XXV (XXV) It can be carried out by the reaction with an activated trifluoromethanesulfonic reagent e.g. anhydrous trifluoromethanesulfonic acid in a suitable solvent such as methyl chloride, chloroform or carbon tetrachloride in the presence of a suitable base such as triethylamine, pyridine or 2,4,6-collidine at a reaction temperature of between -78 ° C. and the ambient temperature. (iv) The conversion of the compound of the formula XXV to the compound of the formula XXVI can be carried out by (XXVI) a) Hydrogenation using a catalyst containing palladium, platinum or nickel in a suitable solvent such as ethanol, methanol or acetic acid and at a reaction temperature between + 20 ° C and + 120 ° C or b) A reaction in a suitable solvent such as methanol in the presence of ammonium formate such as triethyl ammonium formate and Pd / C at a reaction temperature between + 20 ° C and reflux. (v) the conversion of the compound of formula XXVI to the compound of formula XXVII (XXVII) It can be carried out by the reaction of compound XI (XI) Where Lg is an indicator of an absent group, e.g. a halogen such as the chloride, bromide or iodide, or an alkane- or arenesulfonyloxy group such as the p-toluenesulfonyloxy group R; is hydrogen, alkaline C-C. or C3-C 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, e.g. KC03, NaHC03 or KOH, and the reaction can occur between + 20 ° C and + 150 ° C. During the cyclic reaction of XXVI, hydrolysis of the ester may occur. xxvpi) (vi) The hydrolysis of the compound of formula XXVII can be carried out under acidic conditions using acids such as H 2 SO 4, HCl, HBr, in a suitable solvent such as H 2 O, ethanol, methanol, acetic acid or mixtures of these at a temperature between + 20 ° C and reflux or under basic conditions using bases such as NaOH or KOH in a suitable solvent such as H20, ethanol, methanol or mixtures of these at a temperature of + 20 ° C and reflux, resulting in a compound of formula XXVIII, wherein R: is hydrogen, C- or C3-C-cycloalkyl. (vii) Where R: is hydrogen, the protection of a compound of formula XXVIII as a compound of formula XXXIX where R- is a protecting group (xxv) (XXIX) It can be carried out by reaction with a suitable reagent such as dicarbocate di-tert-butyl in a suitable solvent, e.g. Methyl chloride, or chloroform, with a suitable base such as triethylamine or KC03 and a temperature between -20 ° C and + 60 ° C. 4. The conversion of a compound of formula XXX to a compound of formula XXXI xxx xxxi It can be carried out by a) The hydrolysis of the nitrile in a compound of the formula XXX in a suitable solvent such as aqueous methane or aqueous ethanol in the presence of a suitable base such as NaOH or KOH at a reaction temperature of between room temperature and reflux, followed by b) The hydrolysis of said amide formed and the ketal under acidic conditions in a suitable solvent such as aqueous methanol, aqueous ethanol or water in the presence of a suitable acid such as HCl or HBr at a temperature of reaction between room temperature and reflux. (ii) The conversion of a compound of formula XXXI to a compound of formula XXXII XXXÜ It can be carried out by a reaction with a suitable azide such as sodium azide in a suitable acid or mixtures of acids such as H_SO and acetic acid at a reaction temperature between 0 ° C and + 50 ° C ( iii) The conversion of a compound of formula XXXII to a compound of formula XXXIV XXXIII XXXIV It can be carried out by a reaction with 1-benzylpiperazine in a suitable solvent such as N, N- 'dimethylformamide, dimethylsulfoxide or acetonitrile in the presence of a suitable base such as KOH or KoC03 at a reaction temperature of between +50 ° C and + 150 ° C (XXXV) (iv) Hydrolysis of a compound of formula XXXIV to a compound of formula XXXV can be carried out under acidic conditions using acids such as H2SO4, HCl, or HBr in a suitable solvent, e.g. H20, ethanol, methanol or mixtures thereof, and the reaction may occur between + 20 ° C and + 100 ° C or under basic conditions using bases such as NaOH or KOH in a suitable solvent, e.g. H20, ethanol, methanol, or mixtures of these, and the reaction can occur between + 20 ° C and + 100 ° C (xxxvi) (xxxvp) (v) Halogenation of a compound of formula XXXVI to a compound of formula XXXVII where Hal indicates bromine, chlorine or iodine can be carried out by a reagent such as IC1 or Br, Cl2 or SO Cl with 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. (vi) The conversion of a compound of formula XXXVII to a compound of formula XXXVIII (xxxvm) It can be carried out by a metal-halogen exchange, in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using suitable lithium alkyl or metal, e.g. butyllithium, or the corresponding curved lithium or magnesium, followed by a treatment with carbon dioxide at a reaction temperature between -78 ° C and at room temperature.

Methods of preparation of the final product Another object of the invention is a process A (i), A (ii), A (iii), B (i), B (ii) or for the preparation of a compound of general formula I by Ai) Acylation, in the case where R: is a C-C alkyl or a C3-C6 cycloalkyl, and is NR; C0, R? is hydrogen and X and R3 are as defined in the general formula I above, of a compound of formula A, (A) (I) With an activated carboxylic acid R3-COLg: where Lg is a starting group or by the use of a carboxylic acid R3-COOH with an activation reagent.

In this way, acylation according to process A (i) can be carried out with an appropriate activated carboxylic acid, R3COLg: wherein said R3 is as defined above and Lg is a starting group, such as a halogen, e.g. chlorine, in a suitable solvent such as methyl chloride or chloroform with a suitable base, e.g. a trialkylamine such as triethylamine, at a temperature of -20 ° C and the reflux temperature or by using a carboxylic acid, R-, C00H wherein said R_ is so defined with an activation reagent, e.g. N, N'-carbonyldumidazole, N, N'-dicyclohexylcarbodnmide or diphenylphosphmic chloride, with a suitable base such as N-methyl orfolma 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 ° C A (ii) Acylation, in the case where R. is hydrogen, Y is NR; CO, R; is hydrogen, R is a protected group and X and R3 are so defined in the general formula I above, of a compound of formula B (B) (I) 0 With activated carboxylic acid R-COLg? where Lg: is a protected group or by the use of a carboxylic acid R; -COOH with an activation reagent, followed by the extraction of a protected group R-: In this way, Acylation according to the process A (ii) can be carried out with an appropriate activated carboxylic acid, R3C0Lg; wherein said R3 is as defined and Lgi is a starting group, such as a halogen, oe.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base, e.g. a trialkylamine such as triethylamine or using a carboxylic acid, R.COOH wherein said R. is so defined, with. an activation reagent, e.g. N, N'-carbonyldiimidazole, 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 conducted at a temperature between + 20 ° C and + 150 ° C, followed by extraction of the protected group R. by hydrolysis in a suitable solvent such as methyl chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature of between + 20 ° C and + 60 ° C.

A (iii) The debenzylation, in the case where R- is a C-C alkyl or a C-C-cycloalkyl, and the said R_ as defined in general formula I above and R. below is alkyl C-C, cycloalkyl C-C, (CH). OH where m is 2-6 or COR8, of a compound of the formula la, followed by: a) Hydrogenation, d) Alkylation, c) Alkylation and extraction of a protected group or d) Acylation: (Ia) a > Thus, in the case where R. is H the hydrogenation a) the said compound of the formula can be carried out using a catalyst such as palladium, platinum or nickel in a suitable solvent such as acetic acid or Ethanol at a temperature d. reaction between + 20 ° C and + 120 ° C, or a reaction in a suitable solvent such as methanol in the presence of an ammonium formate and Pd / C at a reaction temperature between + 20 ° C and reflux.

In the case where R is a C -.- C alkyl. or cycloalkyl C.-C. the debenzylation is followed by the alkylation b) above using a suitable alkylation reagent such as R; -Lg where Lg is a suitable starting group, e.g. a halogen such as chlorine, bromine or iodine, or an alkane- or arenesulfonyloxy group such as the p-toluenesulfonyloxy group and R; it is a C-Cc alkyl. The reaction can be carried out in a suitable solvent such as N, N-dimethylformamido, acetone, acetonitrile tetrahydrofuran with a suitable base such as K, C03, NaHC03, NaOH or a trialkylamma such as triethylamine. The reaction can be conducted at a temperature between + 20 ° C and + 120 ° C or, Reductive alkylation with a compound R ^ -CHO, donate R is hydrogen or a C -CD alkyl, or with a cyclic acetone C_- C, in the presence of a reducing agent such as sodium c-borohydride, sodium borohydride or catalytically with H2 and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent, eg tetrahydrofuran, dioxane, methanol or ethanol. The donor proton such as p-toluenesulphonic acid can be used to catalyze the formation of the amine / enamine and adjust the pH to slightly acid by an appropriate acid such as acetic acid can be accelerated the reaction.

In the case where R is (CH) OH? m is 2-6, the aesbenzylation is followed by the a) ciation above by using a suitable reagent such as Bn (CH) -Lg where Lg is a suitable group, eg e.g. a halogen such as chlorine, bromine or iodine, or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and R is C -C alkyl. The reaction can be carried out in a suitable solvent such as N, N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base such as KC03, NaHCO3, NaOH or a tialkylamine such as a triethylamine and can be conducted at a temperature between + 20 ° C and + 120 ° C. The reaction is followed by extraction of a protected group, such as a benzyl group, by hydrogenation using a catalyst such as palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature of between + 20 ° C and + 120 ° C, or a reaction in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a temperature between + 20 ° C and reflux.

In the case where R is COR the debenzylation is followed by the acylation of the aforementioned using an appropriate activated carboxylic acid, R-COLg. where said R is so defined and Lg. is a split group, such as a halogen, e.g. chlorine, in a suitable solvent such as methyl chloride, chloroform, N, K -carbonyldumidazole or N, N-diemthylformamide with a suitable base, e.g. a tpalkyl such as triethylamine or by using a carboxylic acid, R..COOH where R "is defined as the aforementioned, with an activating reagent, e.g. N, N -carbonyldumidazole, N, N'-dicyclohexylcarbodiimido or diphenylphosphonic chloride, with a suitable base such as N-methylmorpholino in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran and the reaction can be conducted at a temperature from among + 20 ° C and + 150 ° C.

Bi) The reaction, in case where R; is a C-C alkyl or a C3-C cycloalkyl., Y is CONR;. X, R; and R3 as defined in said general formula I, an activated carboxylic acid of a compound of formula C, (C) (I) With an aniline or amine HNR R In this way, the conversion according to the process B (i) of a compound of the formula C can be carried out by the activation of the acid of a functional compound such as the halide of acid such as the acid chloride or using an activating reagent such as N, N '-carbonyldiimidazole or N, -dicyclohexylcarbodiimide in a suitable solvent, eg Methyl chloride, chloroform, toluene, N, -dimethylformamide, dioxane or tetrahydrofuran, followed by the addition of an appropriate amine or aniline HNR; R3 and the reaction can occur between 0 ° C and + 120 ° C B (Ü) The reaction, in the case where R; it's hydrogen, and it's NR2C0, R is a protecting group and X, R and R- as defined in general formula I above, an activated carboxylic acid of a compound of formula D (D) s) With an aniline or amine HNRR3, followed by extraction of the protected group Rc.

In this way, the conversion according to the process B (n), of a compound of the formula D, can be carried out by the activation of the acid to a compound of the function such as an acid halurc such as the acid chloride. or using an activating reagent such as N, N '-carbonyldumidazole or? t, Nd? c? clohex? lcarbod? im? in a suitable solvent, eg Methyl chloride, chloroform, toluene, N, -dimethylformamide, dioxane or tetrahydrofuran, followed by the addition of an appropriate amine or aniline NHR2R and the reaction may occur between 0 ° C and + 120 ° C, followed by extraction of the protected group R- by methods known to a person skilled in the art such as hydrolysis in a suitable solvent such as methylene chloride or chloroform with a suitable acid, eg trifluoroacetic acid, at a temperature between + 20 ° C and + 60 ° C.

The reaction, in the case where R_ is C: -C alkyl or C-C cycloalkyl, Y is NR: CONR, R_ is hydrogen and X and R3 as defined in said general formula I, a compound of formula A , (A) (I) With an appropriate azide in the presence of the carboxylic acid, R ^ COOH.

In this way, the reaction according to process C can be carried out with an appropriate azide such as diphenylphosphoryl azide in the presence of the carboxylic acid, R3COOH where said R3 is so defined in a suitable solvent such as acetonitrile and acetonitrile. The reaction can be conducted at a temperature between + 20 ° C and the reflux temperature.

Intermediaries intermediaries Another object of the invention is a compound considered in the formula Where X = N 0 CH; Z = NH; o COOH R: is H, C-C alkyl. or C-C cycloalkyl.

The invention is illustrated but not restricted to the functionalities of the subsequent examples Examples of functionalities Example 1 (R) -3-yl, y7-D? Benz? Lam? No-5-methox? -3,4-d? H? Dro-2H-l-benzopyran.

(R) -3-Ammo-5-methoxy? -3, -dihydro-2H-l-benzopranol (2.6 g, 14 mmol), K: CO-. (7. g, 51 mol), benzyl bromide (6.0 g, 35 mol) and an amount of potassium iodide catalyst was mixed in acetonitoplo (100 ml) under nitrogen. The mixed reaction is refluxed for 72 hrs. The solvent is extracted with water, and the residue is partitioned between diethyl ether and a solution of 2 M NH. The layers were separated, and the aqueous phase was extracted twice with diethyl ether. The ether layers were combined and dried (MgSO). The solvent was extracted m vacuo to give a yellow oily residue which was purified by flash chromatography with silica gel (exhaustion solution: methylene chloride) providing 3.2 g (64% yield) of the title compound: EIMS (70eV) m / z (relative intensity) 359 (91, Mb.) The HCl salt was precipitated from diethyl ether at 0 ° C and then recrystallized from ethanol / diethyl ether.The hygroscopic crystals began to dissolve at 100 ° C and finally dissolved between 118 ° C and 120 ° C; [a] 2 O ~ 2C '(c 0.3, methanol).

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

The title compound was synthesized according to the procedure described for the corresponding (R) -enantiomers: [a] "D (measured in the free base) + 116 ° (c 1.0, chloroform).

Example 3 (R) -3-N, N-Dibenc? Lam? No-5-hydrox? -3,4-dihydro-2H-l-benzopyran.

(R) -3-? T,? '- Dibenz? Lam? No-5-methoxy-3, 4-d? H? Dro-2 / l-benzopranol hydrochloride (1.6 g, 4.0 mol) It was dissolved in methylene chloride (40,000 ba or nitrogen, and the solution was cooled to -70 ° C.) A boron tribromide solution (1.8 g, 7.3 mol) in methylene chloride (25 ml) was added dropwise. for 5 min.The temperature was then allowed to slowly reach 0 ° C, and the reaction was stirred overnight.The reaction mixture was carefully poured into a saturated solution of NaHCO 3 with stirring.The layers were separated and the The solvent was extracted in vacuo to give a brownish oily residue which was purified by flash chromatography with silica gel (depletion solution: chloride of methylene) yielding 0.14 g (98% "." .. yield) of the title compound: [a] ^ D "(c 0.1, methanol); EIMS (70eV) m / z (relative intensity) 345 (100, Mb.

Example 4 (S) -3-N, N-Dibenc? No-5-hydrox? -3,4-dihydro-2H-l-benzopyran.

The title compound was synthesized according to the corresponding process described (R) -enantiomer: [ab "D ~:" "(c 1.0, chloroform).

Example 5 (R) -2- (3-tf, tf-D? Benc? La? Mno-3,4-d? H? Dro-2H-l-benzop? Ran-5? Lox?) -2-met? lpropanam? da.

(R) -3-N, ND? Benz? Lammo-5-h? Drox? -3, -d? H? Dro .2H-1-benzopyran (35.4 g, 100 mol.sup.1 were dissolved in 1,4-d? oxane anhydride (350 ml) under nitrogen A dispersion of sodium hydride (60-65% in oil, 5.33 g, 130 mol) was added in portions The mixture was stirred for 2 h at room temperature. 2-methylpropanamide (17.9 g, 110 mol, described in Coutts, IG C .; Southcott, MRJ chem .. Soc. Perkm Trans. 1, 1990, 767-771) was added to the greenish dark solution and heated After refluxing with stirring, a small amount of water was added, the solution was decanted, and the solvent was extracted m va cuo.The residue was subdivided between ethyl acetate (350 ml) and a saturated solution. NaHCO (50 mL) The organic layer was dried (MgSO) and the solvent was extracted with water to give a brownish residue which was chromatographed on a small column of silica gel (depleting solution: hexane / ethyl acetate; 55:45) sum by ingesting 27.6 g (64% yield) of the title compound as a white solid: mp 132-134 ° C; [a D "(c chloroform); EIMS (70eV) m / z (relative intensity) 430 (6, M).

Example 6 (S) -2- (3-tf, .N-Dibenzylamino-3,4-dihydro-2H-l-benzopyran-5-yloxy) -2-methylpropanamide.

The title compound was synthesized according to the procedure described for the corresponding (R) -enantiomer: [a] "D *" "(c 1.0, chloroform).

Example 7 (i?) -5-Am? no-3-JV, JV-dibenzylamino-3,4-dihydro-2H-l-benzopyran. 1, 3-D? Met? L-3, 4, 5, 6-tetrahydro-2 (? H) -pipmidone (31 ml) was added to a stirred solution of (Rl -2- (3-N. Nd) ? oenz? lam? no-3-, 4-d? h? dro-2H-l-benzop? ran-5? lox?) -2-methylpropanamido (31.0 g, 72.0 mol) in anhydrous N, N-dimethylformamide (310 ml) ba or nitrogen Sodium hydride (60-65% in oil, 5.76 g, 144 mol) was added in portions The reaction mixture was heated to 100 ° C and stirred for 16 hrs. it was cold-treated, and the solution was subdivided between acetate ethyl (500 ml) and a 2 M NH solution (300 ml), the layers were separated, and the aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layers were dried (MgSO) and concentrated by vacuo to give a brownish oil.The material obtained was dissolved in ethanol (400 ml). To a solution of 6 M HCl (500 ml) was added, and the mixture was added. The reaction was heated to reflux at 85 [deg.] C. After stirring overnight, the mixture was allowed to cool to 35 [deg.] C., The ethanol was concentrated to vacuo, and the toluene was added to the residual aqueous solution. The mixture was cooled in ice, and a conc. The NH- was added slowly with stirring. A material barely formed. The two-phase alkaline system gave way in a separatory funnel, and the soluble material was treated with a 2 M NH solution, and ethyl acetate. Eventually, all the material dissolved and this was combined with the available mixture in two phases. The layers were separated, and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic layers were dried (MgSOJ), and the solvent was subtracted m vacuc to give a brownish oil which was purified on a small column of silica gel (depleting solution: hexane / ethyl acetate: 80:20) yielding 19.0 g (72% yield) of the desired compound as a slightly yellow oil The product slowly crystallized standing on the refrigerator: mp 99-101 ° C; [ab D ** - "'(c 1.0, chloroform); S (70eV) m / z (relative intensity) 344 (36, M).

Example 8 (S) -5-Am? No-3-ylf, _V-d? Benc? Lam? No-3,4-d? H? Dro-2H-l-benzopyran.

The title compound was synthesized according to the procedure described for the corresponding (R) -enantiomer: [a] cD "(c 1.0, chloroform) An analytical sample was recrystallized from diethyl ether / petroleum ether: p 101-103 ° C.

Example 9 (R) -3-iV, iV-D? Benc? Lam? No-5- (4-met? Lp? Peraz? Nl-? L) - 3, 4-d? H? Dro-2H-l-benzop ? For a solution of (R) -5-ammo-3-N. N-d? Benz? Lammo-3, 4-d? H? Dro-2H-l-benzop? Rano g. 8.30 mol) in a mixture of water in acetonitopl (120 ml) were added sodium iodide (69 mg 0.42 mol)? -methyl-bis (2-chloroetyl) amine hydrochloride (3.20 g, 16.6 mol. With stirring. clean solution of heating until refluxing After 7 hours of stirring, the? aHCO (700 mg, 8.30 mol) was added, and the reaction mixture was further stirred for 11 h.Other portion of? aHCO (700 mg, 8.30 mol) was added followed by a continuous reflux.After 6 hrs, a final portion of NaHCO; (350 mg, 4.15 mol) was added, and the reaction mixture was stirred for 6 more hrs (30 hrs. The mixture was cooled in an ice bath, and a 2M NaOH solution (20 ml) was added with stirring.The two phase system was stirred by minutes. after the solvent was removed under reduced pressure until precipitation occurred. The aqueous residue was extracted with diethyl ether (150 ml), the layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 50 ml). The combined ether layers were dried (mgS0), and the solvent was removed in vacuo. The crude product was purified by column chromatography with silica (exhaustion solution: chloroform / ethanol; 95.5: 4.5 + 0.5% NH concentration) yielding 2.39 g (67% yield) of the title compound as a colorless oil: [a] -D "" '(c chloroformol, EIMS (70eV) m / z (relative intensity) 427 (0.3 M').

Example 10 (S) -1- (3-N, ND? Benc? Lamino-3,4-dihydro-2H-l-benzop? Ran-5-yl) -4-methylp? Peraz? No-2, 6- diona - - Example 10 (S) -1- (3-tf, tf, Dibenzylamino-3,4-dihydro-2H-lbenzopyran-5-yl) -4-methylpiperazine-2,6-dione.

For a dispersion of N-methyliminodiacetic acid (6.90 g, 46.9 mol) in tetrafuran anhydride (575 ml) was added 1,1 '-carbonyldiimidazole (15.2 g, 93.0 mol), and the mixture was heated to reflux for 2 hrs. under nitrogen. A solution of (S) -5-amino-3-N, N-dibenzylamino-3, -dihydro-2H-l-benzopyran (15.0 g, 42.7 mol) in tetrahydrofuran (120 ml) was added with stirring for 0.5 hrs. The reaction mixture was heated to reflux for 28 hrs., Then allowed to cool, and the solvent was extracted in vacuo. The residue was purified on a small column of silica gel (exhaustion solution: methylene chloride and ethyl acetate) yielding 14.1 g (71% yield) of the title compound as a light yellow solid: mp synthesized > 60 ° C; [a] 21 D + 89 ° (c chloroform); EIMS (70eV) (relative intensity) 455 (8, M +).

- - Example 11 (S) -3-N, iif-Dibenzylamino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran.

For a stirred solution of (S) -1- (3-N, N-dibenzylamino-3,4-dihydro-2 H -l-benzopyran-5-yl) -4-methylpipetazine-2,6-dione (25.4 g, 55.8 mol) in anhydrous diethyl ether (800 ml) added in lithium aluminum hydride (9.30 mg, 246 mol) in portions. The reaction mixture was heated for 6.5 h to reflux under nitrogen and stirred overnight at room temperature. The mixture was cooled (in an ice bath), and water (10 ml) was added followed by a 15% aqueous solution of NaOH (81 ml) and another portion of water (30 ml). The precipitate was filtered out and washed with some portions of hot tetrahydrofuran. The organic layers were combined, and the solvent was extracted in vacuo. The residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol; 95: 5 + 0.5% + 0.5% conc NH3) yielding 13.6 g (57% yield) of the title compound as a slightly yellow oil: [a] 25D + 63 ° (c 1.0, methanol, EIMS (70eV) (relative intensity) 427 (5, M +). - 6- Example 12 (R) -3-Amino-5- (4-methyl-piperazin-1-yl) -, 4-dihydro-2H-1-benzopyran. For a solution of (S) -1- (3-N, N-dibenzylamino-3,4-dihydro-2H-1-benzopyran (2.34 g, 5.47 mol) in anhydrous methanol (100 ml) were added palladium (10%) ) on activated carbon (0.86g) and ammonium formate (2.76 g, 43.8 moles) under nitrogen.The reaction mixture was heated to 50 ° C with stirring overnight.The solution was filtered through Celite® The solvent was extracted in vacuo The residue was subdivided between a 2 M NH 3 solution (20 ml) and ethyl acetate (100 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50). ml) The combined organic phases were dried (Na2SO4), and the solvent was extracted in vacuo to give 1.21 g (90% yield) of the title compound as a pale yellow oil: [a] D15 (c 1.0, chloroform); EIMS (70eV) m / z (relative density) 247 (6, M +).

Example 13 (S) -3-Amino-5 (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran.

The title compound was synthesized according to the procedure described for its corresponding (R) -enantiomer: [a] 21 D "15 ° (c, chloroform).

Example 14 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-morpholinobenzamide.

A solution of 4-morpholinobenzoic acid (380 mg, 1.83 mol, described in: Degutis, J., Rasteikiene, L., Degutiene, A. Zh.

Org. Khi m. 1978, 14 (10), 2060-2064) and 1,1'-carbanyldiimidazole (310 mg, 1.92 mol) in N, N-dimethylformamide anhydride (12 ml), were stirred at 75 ° C for 30 min. The mixture was then allowed to cool a solution (5) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (430 mg, 1.74 mol) which in N N-dimethylformamide (8 ml) was added. The reaction mixture was stirred at room temperature for 3 days. Another portion of 1, 1-carbonyldiimidazole (57 mg, 0.35 mol) was added, and the mixture was stirred for 3.5 h additionally. The solvent was extracted in vacuo, and the residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol: 93: 7 + 0.5% NH3) yielding 513 mg (68% yield) of the title compound as a white solid: p.t. 210-212SC ^ 2_ 1450 (C Io, chloroform) 17, (77? 7) m / 2 (relative intensity) 435, «^ JD (65, mt) EIMS (70cV) m / 2 (relative intensity) 436 (65 , mt) Ejenplo 15 (R) -N- [5- (4-methylpiparazin-1-yl) -3,4-cli-c-ro --- Hl-benzopyran-3-yl] -4-porfolirichaprazamide. The title compound was synthesized according to the procedure described for its corresponding enantiomer (S) [a] aD + 145 ° C (C 1.0, chloroform).

Ejatplo 16 (S) - - [5- (4-itethyl-piperazin-1-yl) -3,4-dihyo-O-H-1-benzyl) -? Iran-3-yl] -4-piperanedibenzamide.

A suspension of 4-piperidinobenzoic acid (276 mg, 1.35 prnol, described in: Eringa, WD; Janssen, MJ Red., Chim. Pays-Bas 1968, 87 (12), 1372-1380 and 1, 1 '-carbonyl .imidazole (229 mg, 1.41 mmol) in anhydrous N ^N-dimethylphopnamide (11 ml) was placed in an oil bath at 75 ° C. After stirring for 45 min, the mixture was allowed to cool. 5. -3-apvin-5- (4-methylpiperazin-1-yl) -3, 4- oul-idrO-2H-l-benzopyran (317 mg, 1.28 pnnol) in N, Not * imetilf? J? Amic? (5 ml) were added, and the mixture was stirred at room temperature for 40 h.Another portion of l, l '-carjDonildii ddazole (83 mg, 0.51 itmol) was added, and the reaction was stirred for 3 days. At the same time, the reaction was not completed and a final amount of 1, 1'-C-arbonylcylimidazole (42 mg, 0.25 mmol) was added.The reaction mixture was heated at 50 ° C for 3 hrs after The solvent was extracted in vacuo.The residue was purified by a column chromatography of silica (depletion solution: chloroform / ethanol; 92: 8 + 0.5% NH3) yielding 202 mg (36% yield) of the title compound as a white solid: mp 178-180 ° C; [a] 22D "159 ° (c 1.0, chloroform); EIMS (70eV) m / z (relative intensity) 434 (35, M +).

Example 17 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-butoxybenzamide. A solution of 4-butobenzoic acid (650 mg, 3.35 mol) in thionyl chloride was heated to 50 ° C for 15 min after the mixture was allowed to cool to room temperature. Excess thionyl chloride was extracted under reduced pressure, and the residue was evaporated with two portions of toluene. The acid chloride was obtained as a brownish oil. A portion of the acid chloride (150 mg, 0.705 mol) was dissolved in methylene chloride (5 ml) and added to an ice-cooled solution of (S) -3-amino-5- (4-methylpiperazine-1). il) -3,4-dihydro-2H-l-benzopyran (159 mg, 0.643 mol) and triethylamine (134 μL, 0.960 mol) in methylene chloride anhydride (20 ml). The ice bath was removed, and the temperature was allowed to reach room temperature. The reaction mixture was washed with a saturated solution of NaHCO 3 (10 ml), dried (mgSO 4), and the solvent was extracted in vacuo. The residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol; 92: 8 + 0.5% conc NH3) yielding 2900 mg (74% yield) of the title compound as a white solid: mp 192-193 ° C; [a] 22D ~ 11 ° (c 1.0, chloroform); EIMS (70eV) m / z (relative intensity) 423 (52, M +).

Example 18 (J?) - N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-butoxybenzamide. The title compound was synthesized according to the procedure described by this corresponding (S) enantiomer: [a] 1D + 10 ° (c 1.0, chloroform).

Example 19 (R) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-tri-loromethyl-benzamide. A mixture of 4-trifluoromethylbenzoic acid (195 mg, 1.02 mol) in thionyl chloride (5 ml) was heated to 50 ° C for 20 min. and so for 10 min. until reflux. The mixture was allowed to cool after the excess thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 ml) and added in an ice-cooled solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3, 4-dihydro-2H-1-benzopyran (230 mg, 0.930 mol) and triethylamine (194 μL, 1.39 mol) in anhydrous methylene chloride (20 ml) with stirring. The reaction mixture was allowed to reach room temperature and washed with a saturated solution of NaHCO 3. After drying (MgSO 4) and evaporating the solvent in vacuo, a crude product was obtained which was purified by column chromatography with silica (exhaustion solution: chloroform / ethanol); 92: 8 + 0.5% conc. NH3): This procedure obtained 214 mg (55% yield) of the title compound as a white solid: mp 212-214 ° C; [a] 2d "73 ° (C 1.0, chloroform), EIMS (70eV) m / z (relative intensity) 419 (100, M +).

Example 20 (R) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -trifluoromethyl-benzamide.

The title compound was synthesized according to the procedure described for ßu corresponding enantiomer- (corresponding S.: [a] 21 D + 74 (c 1.0, chloroform).

Example 21 (R) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2-yl-1-penzopyran-3-yl] -2,4-dimethoxy-benzamide. A solution of 2,4-dimethoxybenzoic acid (185 mg, 1.01 mol) in thionyl chloride (5 ml) was heated to 55 ° C. min. The excess thionyl chloride was extracted in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was thus dissolved in anhydrous methylene chloride (5 ml) and added to an ice-cooled solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3, 4- dihydro-2H-l-benzopyran (228 mg, 0.920 mol) in anhydrous methylene chloride (20 ml) with stirring. The precipitated product was dissolved by the reaction of triethylamine (193 μL, 1.38 mol) to give a slightly yellow solution. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was washed with a saturated solution of NaHCO 3, drying (MgSO 4), and the solvent was extracted in vacuo. The residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol: 92: 8 + 0.5% conc NH3) yielding 268 mg (71% yield) of the title compound as an oil: [a ] 21D ~ 91 (c 1.0, chloroform): EIMS (70eV) m / z (relative intensity) 411 (4, M ") The base (238 mg, 0.578 mol) was dissolved in anhydrous diethyl ether (10 ml) under Nitrogen and cooled in an ice bath A solution of HCl in diethyl ether (3 M, 0.5 ml), diluted with diethyl ether (5 ml), was added dropwise with stirring The HCl salt was filtered, washed with diethyl ether, and dried in vacuo yielding 187 mg (60% yield) of the product as a white powder: mp synthesized > 44 ° C.

Example 22 (R) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-W, W-diethylaminobenzamide. A solution of 4-diethylaminobenzoic acid (189 mg, 0.978 mol) and 1,1 '-carbonyldiimidazole (166 mg, 1.02 mol) in anhydrous N, N-dimethylformamide (5 ml) was stirred at 75 ° C for 45 min. The mixture was allowed to cool, and a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (230 mg, 0.930 mol) in N , N-dimethylformamide (8 ml) were added. The reaction mixture was stirred at room temperature for 7 days. The solvent was removed in vacuo, and the residue was purified by an o-lithium c-taratography can < = rí "Hp-> (scè cdón cte agstamsito: cl oraf omp / ets-xl; 92: 8 + 0.5% Mi), suwiis iHrrb 234 pg (60% cte repi-? rái = pt.0) ctel caipu? Sto of the title chorus a solid white, mp 218-ZL9 ° C; [a] aD "Ißc (c 1.0, cüf-pha-tD); EÜVE (70eV) m / z (relative j? Tatsirted) 422 (29, M. l ^ ep_-Lo 23 (R) -N ^ [5- (4-pEt-Upipa3zán-l-il. -3, -dihidt- > -.2rH. - _ ^^ The title subject is -between -Ob agreed to the procB iirasp or dsscrito for its ° C (c 1.0, clcjrofariiD).

Ejßppk3 2i (S) -N- 5- (4 ^? Eti-F-fe-azin-l-il) -3,4-dáiúáos-2 l-bßcaq ^ X? - ^ il] -GJEact-2raß atam3a. To a stirred, ice-cold amphcalate, cte (S) -3-amr? O-5- (4-peti lpipRrazi ni-il) -3, 4-dil idro- ^ l-b3T2q3Irano (230 pg, 0.930 rarol) and txieti] -atuxa (194 | JL, 1.39? DI) in anhydrous cte petilaxyl chloride (10 pL), chloride or 2-phiol-Lo (101 μL, 1.02 rarol) was added under nitrogen. The ice cube is removed and the reaction mixture is allowed to reach its equilibrium temperature. The mixture is washed with a solution 2? oe Mi, it dries eLirpina in vacuo. The reranale will go away for a short period of time (with an anaerobic filter, an approximate solution: clacoyam, 92: 8 + 0.5% for M cxeptracb) to prcr-xar 249 ng (rerrlimietto) cte 79%) cpt cptpuesto ctel title COTO a white solid: p.f. sip etiza a > 50 ° C; [a] aD'ßc (c 1.0, cLcrofaptD); EH B (70eV) / z (intaisid? D relative) 341 (52, lí).

Ejaip-Lo 25 d meti 1atarrijgi ---? P-jda. A solution of acid (190 mg, 1.15 mmol) and 1, 1-carbonylcliimidazole (205 mg, 1.26 pmol) in N-dimethylphoimiamide arihydride (5 ml) was stirred at 75 ° C for 35 min. The mixture was allowed to cool, and a solution of (S) -3-anino-5- (4-met.i-lpipera i -l-yl) -3, 4-o * i idro-2H-l-benzopyran (271 mg, 1.10 pmol) in N, Ndi? tetylf? J t -measure (5 ml) were added.

The reaction mixture was stirred to the arperated tarperatrira for 4 days. The solvent was removed by vacuum, and the residue was purified by a colloidal crarate chromatography on silica (reaction solution: ¿¿¿¿¿..

% NH_) sumii i = trancb 292 mg (67% of yield) of the title compound was a white solid; p.f. 248-250 ° C; (S) [a] ^ - 5 ° C (C 1.0, chloroform); The B (70eV) m / z (relative intensity) 394 (46, V).

Eg 26 (S) -F- [5- (4-p? AH li arat? N-1 -ii) -3,4-oihia t -. * FM-beri7q_7I ran-3-il] -pirrola-2-C-ai-boxamide A mixture of 1. ' 1 '-carboni 1 di imidazole (360 g, 1.85 pmol) and pyrrole-2-catboxi acid i co (225 mg, 2.03 pmol) in N, N-olrretllfQp ?? 3m.da (8 ml) was stirred at 75 ° C for 45 min. the mixture was allowed to cool, and a solution of (S) (457 irg, 1.85 prrol) in NN-dimeti-1 formamide (10 ml) were added. The reaction mixture was stirred for 7 days at room temperature under nitrogen. The solvent was removed in vacuo, and the residue was extracted with diethyl ether (50 ml) and water (20 ml). The aqueous layer was extracted with another di ethyl ether partition (50 ml). the combined ethereal layers were dried (MgSO4), and the solvent was extracted in vacuo. The residue was purified by column chromatography with silica (exhaustion solution: chloroform / ethanol, 90:10 + 0.5% conc NH3) yielding the title compound as an oil. Evaporation with diethyl ether gave 300 mg (48% yield) of the title compound as a white powder: mp sintered to > 96 ° C; [a] 21 D ~ 82'8 ° (c 1.0, chloroform); EIMS (70eV) m / z (relative intensity) 340 (10, M +).

Example 27 (S) -tf- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -5-methylpyridine-3-carboxamide. A solution of 5-methylnicotinic acid (141 mg, 1.03 mmol) and 1,1 '-carbonyldiimidazole (183 mg, 1.13 mmol) in anhydrous N, N-dimethylformamide (5 mL) was stirred at 75 ° C for 55 min.

The mixture was allowed to cool, and a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (232 mg, 0. 94 mol) in N, N-dimethylformamide (5 ml) were added. The reaction mixture was stirred at room temperature for 28 hrs. The solvent was removed in vacuo, and the residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol; 87:13 + 0.5% NH 3). The product was contaminated with a large amount of imidazole which could be extracted by the following procedure: The mixture is dissolved in diethyl ether (100 ml), washed with water (2 x 20 ml) and treated with brine (10 ml). ). The ether layer is dried (MgSO.), and the solvent is extracted in vacuo to give 119 mg (35% yield) of the title compound as a white solid: mp sinter to > 68 ° C; [a] 21 D ~ 8 ° (C 1.0, chloroform); EIMS (70Ev) m / z (relative intensity) 366 (21, M +).

Example 28 (S) -tf- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -2,4-bis (trifluoromethyl) -enomamide. A solution of 2,4-bis (trifluoromethyl) benzoic acid (195 mg, 0.755 mmol) in thionyl chloride (4 ml) was heated to 55 ° C for 45 min. The excess thionyl chloride was extracted in vacuo, and the residue was evaporated with two portions of toluene.

The acid chloride was then dissolved in anhydrous methylene chloride (5 ml) and added to a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H -l-benzopyran (170 mg, 0.687 mmol) and triethylamine (144 μL, 1.03 mol) in anhydrous methylene chloride (20 ml) with stirring. The reaction mixture was left overnight at room temperature and washed with a 2M solution of NH - - (10 ml) followed by a portion of brine. The organic layer was dried (MgSO4), and the solvent was extracted in vacuo. The residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol, 92: 8 + 0.5% conc NH3) yielding 100 mg (30% yield) of the title compound as a white powder: mp 202 -203 ° C; [a] 21 D "51 ° (c 1.0, chloroform); EIMS (70eV) m / z (relative intensity) 487 (16, M +).

Example 29 (s) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -2-hydroxy-4-methoxy-benzamide. A solution of 4-methoxy-2-acetoxybenzoic acid (232 mg, 1.10 mmol, described in: Schonhofer, JSer Deutsch Chem Ges 1951, 84, 13) in thionyl chloride (5 ml) was heated to 55 ° C. 30 min. The excess thionyl chloride was extracted in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 ml) and added to a stirred solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3, 4-2H- l-benzopyran (248 mg, 1.00 mol) and triethylamine (210 μl, 1.50 mol) in anhydrous methylene chloride (20 ml). The reaction mixture was stirred at room temperature for 2.5 hrs. and then the mixture was washed with a saturated solution of NaHCO 3, dried (MgSO 4), and the solvent was removed in vacuo. The residue was completely dissolved in absolute ethanol (20 ml), and conc. NH3 (5 ml) were added. The mixture was stirred overnight. The solvent was removed in vacuo, and the leftovers were purified by column chromatography with silica (depletion solution: chloroform / ethanol; 92: 8 + 0.5% conc NH3) yielding 120 mg (33% yield) of the title as a white solid: pf sinterizes a > 80 C; [α] D "(c 1.0, chloroform): EIMS (70eV) m / z (relative intensity) 397 (27, M +).

Example 30 (S) -JV- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-trifluoromethoxy-benzamide. A mixture of 4-trifluoromethoxybenzoic acid (254 mg, 1. 23 pmol) in thionyl chloride (5 ml) was heated to 60 ° C for 25 min. The excess thionyl chloride was removed under reduced pressure, and the leftovers were evaporated with two portions of toluene. The acid chloride was dissolved in anhydrous methylene chloride (5 ml) and added to a stirred solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H -l-benzopyran (277 mg, 1. 12 mmol) and triethylamine (234 μL, 1.68 mmol) in methylene chloride (10 mL). The reaction mixture was stirred for 2 hrs. at room temperature and washed with a saturated solution of NaHCO 3. The organic layer was dried (MgSO4), and the solvent was extracted in vacuo. The product was purified by column chromatography with silica (depletion solution: chloroform / ethanol, 92: 8 + 0.5% conc NH3) yielding 248 mg (51% yield) of the title compound as a white solid: mp 192- 193 ° C; [a] 21 D "75 ° (c? .o, chloroform) EIMS (70eV) m / z (relative intensity) 435 (6, M +). Example 31 4- (4-piperidon-l-yl) benzoic acid. A solution of 2M NaOH (10 ml), benzonitrile 4- (8-aza-1,4-dioxaspiio [4, 5] dec-8-yl) (820 mg, 3.36 mmol, described in: Taylor EC; Skotnicki JS Synthesis 1981, 8, 606-608), and ethanol (7.5 ml) was heated to reflux for 3 hrs. The external heating was stopped, and the reaction mixture was stirred overnight at room temperature. The ethanolic solvent was removed in vacuo, and the leftovers were acidified to pH 4 with a 2M HCl solution followed by extraction with ethyl acetate (50 ml). The layers were separated, and the pH was adjusted to pH 6 with a 2M NaOH solution followed by another extraction with ethyl acetate (50 ml). The combined organic layers were concentrated in vacuo, and the solid residue was dissolved in a 6M HCl solution (10 ml). The reaction mixture was heated to 75 ° C for 2.5 hrs. and subsequently at 55 ° C during the night. The temperature rose to 75 ° C for 2 hrs. and the reaction mixture was then allowed to cool. The pH was adjusted to pH 4, and the solution was extracted with ethyl acetate (50 ml). The layers were separated, and another extraction was done at pH 5. The combined organic layers were dried (MgSO4), and the solvent was extracted in vacuo. The crude product was recrystallized from ethyl acetate giving 300 mg (41% yield) of the title compound as yellowish crystals: mp sinter to > 215 ° C; EIMS (70eV) m / z (relative intensity) 219 (100, M +).

Example 32 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2-yl-1-benzopyran-3-yl] -4- (4-piperidon-1-yl) -benzamide. A solution of • 1, 1 '-carbonylimidazole (116 mg, 0. 716 pmol) and acid (150 mg, 0.683 mol) in anhydrous N, N-dimethylformamide (5 ml) was stirred at 75 ° C for 50 min. The mixture was allowed to cool, and the solution of (S) -3-amino-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (161 mg, 0.651 mmol) in N , N-dimet ilformamide (4 ml) were added. The reaction mixture was stirred at room temperature for 8 days. The solvent was extracted in vacuo, and the residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol, 90:10 + 0.5% conc NH3) yielding 54 mg (19% yield) of the compound of the title as a white solid: mp 222-225 ° C (decomposes); [a] 22 D "136 ° (c 0.30, chloroform); TSPMS (70eV) m / z 449 (M + l).

Example 33 (S) -7- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-morpholinobenzenesulfonamide. To a solution of (S) -3-amino-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (120 mg, 0.485 mmol) in anhydrous methylene chloride (10 ml) ) triethylamine (81 μL, 0.582 mmol) and 4- (4-morpholinyl) benzosulfonyl chloride (140 mg, 0.534 pmol, described in: Galliani, G. Eur. Pat. Appl. EP 335,758, 1989, chem. Abstr. 1990, 112, 98374d [125393-22-8]). The reaction mixture was stirred at room temperature for 4 hrs., Washed with a 2M solution of NH3, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography with silica (depletion solution: chloroform / ethanol, 90:10 + 0.5% conc NH3) yielding 141 mg (61% yield) of the title compound as a white solid: mp sinter a > 100 ° C; [a] 22 - - D + 10 ° (c 1.0, chloroform); EIMS (70eV) m / z (relative intensity) 472 (56, M +).

Example 34 4- (hexahydro-l, 4-diazepin-5-on-l-yl) benzoic acid. A solution of 4- (piperidon-1-yl) benzoic acid (281 mg, 1.28 mmol), concentrated acetic acid (2 ml), and concentrated H SO (1 ml) was cooled to 5 ° C. Sodium azide (92 mg, 1.41 mol) was added, and the reaction mixture was stirred at 7 ° C for 42 hrs. A solution with pH 5 of Na0H 2M was added, and the resulting precipitate was filtered and washed with several portions of ice water. Drying in vacuo yielded 272 mg (91% yield) of the title compound as a white solid: mp 285-286 ° C; EIMS (70eV) m / z (relative intensity) 234 (66, M +).

Example 35 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (hexahydro-1,4-diazepin-5-on -l-il) benzamide. A solution of 1,1 '-carbonyldiimidazole (151 mg, 0.934 mmol) and 4- (hexahydro-1, -diazepin-5-on-1-yl) benzoic acid (219 - mg, 0.934 mmol) in N, N anhydrous dimethylformamide (7 ml) was stirred at 75 ° C for 55 min. The mixture was allowed to cool, and a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3, -dihydro-2H-1-benzopyran (210 mg, 0.85 mmol) in N, N-dimethylformamide (3.5 ml) was added. The reaction mixture was stirred at room temperature for 14 days. The solvent was removed in vacuo, and the residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol, 90:10 + 1% conc NH3). The product was crystallized from a mixture of chloroform, ethanol, and ethyl acetate yielding 84 mg (21% yield) of the title compound as white crystals: mp 244-247 ° C (decomposes); [a] 21 D ~ 1 8 ° (c 0.50, chloroform); TSPMS (70eV) m / z 464 (m + l).

Example 36 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -N '- (4-morpholino) enyl urea. To a stirred solution of 4-morpholinobenzoic acid (126 mg, 0.606 mmol) and (S) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (150 mg, 0.606 mmol) in acetonitrile (5 ml) was added diphenylphosphoryl azide (131 μL, 0.606 mmol). The reaction mixture was heated to reflux by 1. 5 hrs and then allowed to cool to room temperature overnight. The solvent was removed in vacuo, and the residue was subdivided between ethyl acetate and a 2 M NH 3 solution. The organic layer was dried (MgSO4), and the solvent was extracted in vacuo. The residue was purified by column chromatography with silica (depleting solvent: chloroform / ethanol, 90:10 + 0.5% concentrated NH 3 supplying 100 mg (36% yield) of the title compound as a white solid: m.p. synthesized a >; 118 ° C taJ ^ D "71 ° C (C 0.5, chloroform); MSTSP 452 (M + l).

Example 37 4-bromo-3-methoxy orfolin-benzene To a stirred liquid paste of 4- (3-methoxyphenyl) morpholine (1.54 g, 7.97 mmol); described in: Skowronska-Ptasinska M .; Verboon W .; Reinhoundt D. N. J. Org. Chem. 1985, 50 (15), 2690-8) and sodium acetate (0.7884 g, 9.56 mmol) in 1,4-dioxane (100 ml) was added a solution of 0.25 M bromine in 1,4-dioxane (25.0 ml, 8.77 mmol) for 45 min. Another portion of the solution of bromine (15.0 ml, 4.00 mmol) and sodium acetate (0.523 g, 6.38 mmol) was added, and the reaction mixture was heated overnight. The solvent was removed in vacuo, and the residue was subdivided between diethyl ether (100 ml) and a 2 M NH 3 solution. The layers were separated, and the aqueous layer was extracted with diethyl ether (50 ml). The combined organic layers were dried (MgSO4), and the solvent was extracted in vacuo. The residue was filtered through a column of silica gel (Depletion solution: chloroform / ethanol, 1: 1 + 1.5% conc.

NH2), and the solvent was vacuumed. The residue was subdivided between methylene chloride and a NH solution. 2 M. After drying the organic layer (MgSO) and removing the solvent in vacuo, an orange oil was obtained which was purified by column chromatography with silica (exhaustion solution: methylene chloride). + 0.5% conc: NH3) supplying 450 mg (21% yield) of the title compound as a white solid: mp 103-104.5 ° C; EIMS (70eV) m / z (relative intensity) 273/271 (56/56, M ').

EXAMPLE 38 2-Methoxy-4-morpholinobenzoic acid A 'a solution of 4-bromo-3-methoxy-1-morpholine inoben (104 mg, 0. 382 mmol) in anhydrous tetrahydrofuran (3 ml) at -78 ° C slowly added n-butyl lithium (solution in hexanes 1.3 M, 325 μL, 0.4 420 pmol) under no or trogen. The cooling medium was exchanged with an ice bath, and the reaction mixture was stirred for 5 hrs. After cooling again to -78 ° C, the carbon dioxide from the evaporation of the dry ice was bubbled through the solution for 10 min. A precipitate formed, and the reaction mixture was allowed to reach room temperature. Diethyl ether and water were added. The mixture was extracted, the layers were separated, and the aqueous layer was acidified to pH 4. The dark blue aqueous solution was extracted several times with diethyl ether and ethyl acetate of a pH 4 at a pH of 6.

The combined organic layers were dried (MgSO), and the solvent was extracted in vacuo affording 60 mg (66% yield) of the title compound as a white solid: mp 158-160 ° C; EIMS m / z (relative intensity) 237 (100, M *).

Example 39 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -2-methoxy-4-m-ardoxy-benzamide. A stirred solution of 1,1 'carbonyldiimidazole (222 mg, 1.37 ntnol) and 2-methoxy-morpholinobenzoic acid (176 mg, 0.740 mmol) in anhydrous N, N-dimethylformamide (5 ml) was heated to 75 ° C for 2 hrs. and allowed to cool. A solution of (S) -3-amino-5- (4-methylpiperazin-1 -3,3-dihydro-2H-1-benzopyran (183 mg, 0.740 mol) N, N-dimethylformamide anhydrous (4 ml The reaction mixture was stirred at room temperature for 5 days.The solvent was removed in vacuo, and the residue was subdivided between ethyl acetate (50 ml) and a 2M NH 3 solution (15 ml). The organic layer was dried (MgSC), and the solvent was extracted in vacuo.The residue was purified by column chromatography with silica (depletion solution: chloroform / ethanol, 93: 7 + 0.5% conc NH3) giving 113 mg ( 30% yield) of the title compound as a colorless foam: [a] ^ D "1: (c 0.5, chloroform); EIMS (70 eV) m / z (relative intensity) 466 (20, M +).

Example 40 4- (4-benzylpiperazin-1-yl) benzonitrile. To a solution of 4-fluorobenzonitrile (3.0 g, tmol) in N, N-dimethylformamide (15 ml) was added 1-benzylpiperazine (4.3 ml, 25 mmol) and potassium carbonate (3.4 g, 25 mmol). The reaction mixture was stirred at 120 ° C for 13 hrs. The solvent was evaporated m vacuo and the residue was subdivided between ethyl acetate (100 ml) and water (15 ml). The aqueous phase was extracted with ethyl acetate (30 ml) and the combined organic phases were washed twice with brine. (10 ml) and dried (MgSO_). The evaporation of the solvent gave 7. 6 g of raw product. Purification of the residue on a column of silica gel using ethyl acetate / methylene chloride (1: 9) as the exhaustion solution supplied 4. 0 g (59% yield) of the title compound as a white solid: mp 104-105 ° C; EIMS (70eV) m / z (relative intensity) 277 (20, M ").

Example 41 4- (4-Benzylpiperazin-1-yl) benzoic acid. 4- (4-Benzylpiperazin-1-yl) benzonitrile (4.0 g, 15mmol) was dissolved in glacial acetic acid (40 ml), 6M hydrochloric acid (50 ml) was added and the reaction mixture was stirred at 100 ° C for 17 hrs. The solvent was evaporated, the residue was suspended in water (10 ml) and the pH adjusted to 3 by the addition of 2 M sodium hydroxide (35 ml). The liquid paste was stirred at 50 ° C for 2 hrs., Cooled and the precipitate was filtered and dried in vacuo to give 4.1 of a crude product. The solid was subdivided between methylene chloride (40 ml) and water (220 ml) with 2 M sodium hydroxide (8 ml). The aqueous phase was washed with methylene chloride (40 ml) and the pH was adjusted to 5 with 2M hydrochloric acid. The aqueous phase was cooled, the precipitate was filtered and dried in vacuo to give 1.6 g (38% yield) of the title compound: mp 226 ° C (dec); EIMS (70eV) m / z (relative intensity) 296 (44, M +).

Example 42 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-benzyl-piperazin-1-yl) -benzamide. A suspension of 4- (4-benzylpiperazm-1-yl) benzoic acid (1.3 g, 4.2 mmol) and 1,1 '-carbonyldiimidazole (740 mg, 4.2 mmol) in N, N-dimethylformamide (30 ml) was added. heated at 75 ° C for 1.5 hrs. The reaction mixture was cooled to 50 ° C and a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3, -dihydro-2H-1-benzopyran (1.0 g, 4.0- n mol) was added. The solution was stirred at 50 ° C for 20 hrs. and the solvent was evaporated in vacuo giving 3.5 of a crude product. Purification by silica gel chromatography using chloroform / methanol / concentrated ammonia 95: 5: 0.5 as the depletion solution gave 1.7 g (80% yield) of the title compound as a pale yellow solid: mp sinter to > 85 ° C; TSPMS m / z (relative intensity) 526 (100, M + 1); [a] "D'I30 ° (c 1.0, chloroform).

Example 43 (S) -tf- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (piperazin-1-yl) -benzamide. (5) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2'-l-benzopyran-3-yl] -4- (4-benzylpiperazin-1-yl) benzamide (1.7 g, 3.2 mmol) was dissolved in methanol (100 ml). Palladium (10%) in activated carbon (510 g) and formate. of ammonium (1.6 g, 26 mol) was added and the reaction mixture was stirred at 50 ° C for 19 hrs. The catalyst was filtered, and removed and the solvent was evaporated, yielding 1.3 g (92% yield) of the title compound as a pale yellow solid: mp > 102 ° C with sintering; EIMS (70eV) m / z (relative intensity) 435 (8, M +): [a] 22 D "1C ° (c 0. 15, chloroform), Example 44 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-acetyl-piperazin-1-yl) -benzamide. (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2-y-1-benzopyran-3-yl] -4- (piperazin-1-yl) -benzamide (460 mg, 1.0 mmol) was added in N, N-dimet i formamide (5 ml) and acetyl chloride (82 μL, 1.2 mol) was added. The solution was stirred at room temperature by 1 hr and the solvent was evaporated in vacuo. The residue was subdivided between methylene chloride (80 ml) and 2 M NaOH (10 ml). The organic layer was washed with brine (5 ml) and dried (MgSO). Evaporation of the solvent in vacuo gave 660 mg of a crude product. Purification by column chromatography with silica using chloroform / ethanol (saturated with ammonia) 15: 1 as the depleting solution gave 330 mg (66% yield) of the title compound as a white solid: mp 88 ° C (dec); EIMS (70eV) m / z (relative intensity) 477 (3, Mb, [a] "D" i 3e (c 1. 05, chloroform).

Example 45 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (morpholinocarbonyl) -benzamide. 4- (Morpholinocarbonyl) benzoic acid (100 mg, 0.43 mmol-; described in: J. Med. Chem. 1994, 37 (26), 4538-4554) and 1,1'-carbonyldiimidazole (76 mg, 0.47 mmol) was dissolved in N, N-dimethylformamide. 3 ml) and heated at 75 ° C for 3.5 hrs. Additionally 1, 1 '-carbonyldiimidazole (36 mg, 0.22 mol) was added and the solution was stirred for 30 min. (S) -amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (100 mg, 0.40 mmol), were dissolved in N, N-dimethylformamide (2 ml), was added and the reaction mixture was stirred for 18 hrs. The solvent was evaporated and the residue was subdivided between ethyl acetate (30 ml) and water (5 ml), the organic layer was washed with water (5 ml) and brine (5 ml) and dried (MgSO). The solvent was evaporated by vacuo giving 180 mg of a crude product, purification by preparative TLC TLC using chloroform / methanol / concentrated ammonia 95: 5: 0.5 and chloroform / ethanol (saturated with NH3) 12: 1 as the exhaustion solution. gave 98 mg (53% yield) of the title compound as a white solid: mp 222 ° C (decomposes); EIMS (70eV) m / z (relative intensity) 464 (68, M +); [a] 22 D ~ 1 ° (c 0.44, chloroform).

Example 46 (S) -2IF- [5- (4-met? Lp? Peraz? Nl-? L) -3,4-d? H? Dro-2H-benzopyran-3-? L) -4- (N, Nd) ? met? lam? nocarbon? l) benzam? da. 4- (N, N-d? Met? Lam? Nocarbon?) Benzoic acid (110 mg, 0.56 mol, described in: U.S. Patent 3,607,918, 1971) was added dropwise to thionyl chloride (500 μL, 6.9 mmol). The reaction mixture was stirred at room temperature for 1 mm and then it was concentrated m vacuo. Excess thionyl chloride was co-evaporated with toluene m vacuo. The crude hydrochloric acid was dissolved in methylene chloride (8 ml) and dropwise added to a solution of (S) -3-ammo-5- (4-met? Lp? Peraz? N-1-? L) -3, -d? H? D-2H-l-benzopranol (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (5 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min and additionally at room temperature for 30 m. The solvent was evaporated -in vacuo yielding 300 mg of a crude product. Purification by preparative TLC on silica using chloroform / ethanol (saturated with ammonia) 10: 1 as the exhaustion solution gave 120 mg (54% yield) of the title compound as a white solid: mp 219 ° C (dec); EIMS (70eV) m / z (relative intensity) 422 (47, Mb; [a] 2: D "12 ° (c 0.42, chloroform).

Example 47 (S) -N- [5- (4-met? Lp? Perazm-l-? L) -3,4-d? H? Dro-2H-l-benzopyran-3-? L] -4- [4 - (2-benc? Lox? Et? L) -p? Peraz? N-1-íl) benzam da. (S) -N- [5- (4-met? Lp? Perazm-l-? L) -3, -d? H? Dro-2H-l-benzopyran-3-? L] -4- (p? perazm-1-? l) benzamide (500 mg, 1.2 mmol) was dissolved in N, Nd? meth? lformamide (5 ml) and potassium carbonate (170 mg, 1.3 pmol) was added. To the mixture was added a solution of 2-benzyloxyethyl mesylate (290 mg, 1.3 mmol) (described in: Beard, CEdward, J; Fried, JUS Patent 3 929 824, 1972) in N, N-dimethylformamide (5 ml. ). The reaction mixture was stirred at 40 ° C for 24 hrs. The solvent was evaporated in vacuo giving 950 mg of a crude product. Purification by column chromatography with silica gel using chloroform / methanol / concentrated ammonia 95: 5: 0.5 as the exhaustion solution provided 154 mg (24% yield) of the title compound as an oil: EIMS (70eV) m / z (relative intensity) 569 (3, Mt).

Example 48 (S) -tf- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- [4- (2-hydroxyethyl) -piperazine-1 -yl] benzamide. (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- [4- (2-benzyloxyethyl) -piperazine-1 -yl] benzamide (150 mg, 0.27 mmol) was dissolved in acetic acid (10 ml) and palladium (10%) on carbon (12 mg) was added. Hydrogenation at room temperature and at atmospheric pressure for 14 hrs is followed by filtration and evaporation of the solvent in vacuo which gave 180 mg of crude product. The residue was subdivided between methylene chloride (60 ml) and 2 M NH3 (5 ml) and washed with brine (5 ml). Drying (MgSO4) solution and evaporation of the solvent in vacuo gave 120 mg of crude material. Purification by preparative TLC on silica, with chloroform / methanol / concentrated ammonia 95: 5: 0.5 as the exhaustion solution, gave 37 mg (29% yield) of the title compound as a white solid: mp 211-212 ° C; EIMS (70 eV) m / z (relative intensity) 479 (8, M +); [a] 22 D "26 ° (c 0.26, chloroform).

PHARMACOLOGY Stimulation with electric field of the release of [3H] -5-HT from the occipital cortex of guinea pigs The [3H] -5-HT is released by the stimulation, with electric field, of the occipital cortex of guinea pigs that had been previously concealed with [3H] -5-HT. This release is similar to that caused by nerve stimulation, that is, the exocytotic release of the serotonergic nerve terminals, depending on the presence of Ca2 + in the incubation medium. The release of 5-HT is regulated at the level of nerve terminals by autoreceptors, in guinea pigs (as in humans) and belongs to the h5-HT_B receptor subtype. In this way, the agonists of the h5-HT? B receptors reduce the amount of [3H] -5-HT released by the electric field stimulation, while the release is increased by the antagonists of this type of receptor. The analysis of compounds with this method is, therefore, a convenient selective classification technique to determine the potency and functional effect of new agonists and antagonists of the h5-HT_B receptor.

Methods and Materials Composition of the Shock Absorber Solution (mM) NaHCO; (25), NaH2P04.H20 (1.2), NaCl (117), KCl (6), MgSO4x7H20 (1.2), CaCl2 (1.3), EDTA Na2 (0.03). The shock absorber is gasified for at least 30 minutes before use. The pH of the buffer is about 7.2 at room temperature, but rises to about 7.4 at 37 ° C.

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

Electrical stimulation of 5-HT release The superfused buffer was collected in 2 mL per fraction. The slices were stimulated with electricity with a pulse train with a frequency of 3 Hz, a duration of 2 ms and a current of 30 mA for 3 minutes in the fourth and thirteenth fractions. The analyzed drugs were added from the eighth fraction, until the end of the experiment.

Results A first electrical stimulation (or with K +) results in the release of a standard amount of [3H] -5-HT (Si). Before the first and second stimulation, the h5-HT_B antagonist is added to the media, which results in an increase in the release (S2), dependent on the dose, after the second stimulation. See Figure 1. The relation S2 / S ?, which represents the percentage of [3H] -5-HT released in the second stimulation (S2) divided by that of the first stimulation (Si), was used to estimate the effects of the drug on the release of the transmitter. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (30)

1. A compound characterized in that it has the formula (I) (I) where X is N or CH; Y is NR2CH2, CH2NR2, NR2CO, CONR2, NR2S02 or NR2CONR2 wherein R2 is H or alkyl of 1 to 6 carbon atoms; Ri is H, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; R3 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms 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 monosubstituted or disubstituted with R and / or R5; wherein R4 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halogen, CN, CF3, OH, alkoxy of 1 to 6 carbon atoms, NR6R7, 0CF3, SO3CH3, S03CF3, S02NR6R7 , phenyl, phenyl-alkyl of 1 to 6 carbon atoms, phenoxy, alkylphenyl of 1 to 6 carbon atoms, an optionally substituted heterocyclic ring, containing one or two heteroatoms selected from N, 0, S, SO and S02, in wherein the substituent (s) is selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl-alkyl of 1 to 6 carbon atoms, (CH2) m0R9 wherein m is a number from 2 to 6 and R9 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl-alkyl of 1 to 6 carbon atoms, and C0R8, an optionally substituted heteroaromatic ring , which contains one or two heteroatoms selected from N, 0 and S • wherein the (s) substituent (s) is selected from alkyl of 1 to 6 carbons ono, cycloalkyl of 3 to 6 carbon atoms and phenyl-alkyl of 1 to 6 carbon atoms, or C0R8; wherein R6 is H, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R is H, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; and Rβ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, CF3, NR6R, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, 0 and S and a heterocyclic ring containing one or two heteroatoms selected from N, 0, S, SO and S02; R5 is H, OH, CF3, 0CF3, halogen, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; and n is a number from 0 to 4; as enantiomers- (R), enantiomers- (5) or a racemate in the form of a free base or in the form of a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, characterized in that Y is NR2C0 or C0NR23.

A compound according to any of claims 1 to 2, characterized in that X is N.

4. A compound according to any one of claims 1 to 3, characterized in that R_ is H or alkyl of 1 to 6 carbon atoms.

5. A compound according to any one of claims 1 to 4, characterized in that R3 is (CH2) n-aryl.

6. A compound according to any one of claims 1 to 4, characterized in that R3 is (CH2) n-aryl which is substituted with R4, which is a heterocyclic or heteroaromatic ring, optionally substituted, containing one or two heteroatoms selected of N, O and S, or C0R8.

7. A compound according to any of claims 5 and 6, characterized in that n is 0.

8. A compound according to claim 6, characterized in that Rβ is NR6R a heterocyclic ring containing 2 heteroatoms selected from N and O.

9. A compound according to any one of claims 1 to 8, characterized in that X is N and Y is NR2C0.

10. A compound according to claim 9, characterized in that X is N, Y is NR2CO and R4 is morpholino or COR8.

11. A compound characterized in that it is (S) -N- [5- (4-Methylpiperazin-1-yl) -3,4-dihydro-2'-l-benzopyran-3-yl] -4-morpholinobenzamide; (S) -N- [5 (4-Methylpiperazin-1-yl) -3,4-dihydro-2J7-l-benzopyran-3-yl] -4-piperidinobenzamide; (S) -N- 5 5 (4-Methylpiperazin-1-yl) -3,4-dihydro-2-yl "-l-benzopyran-3-yl] -4-butoxybenzamide; (S) -N- [5 (4 Methylpiperazin-1-yl) -3,4-dihydro-2H-l-benzopyran-3-yl] -4-trifluoromethylbenzamide; (S) -N- [5 (4-Methylpiperazine-1-yl) -3, 4 -dihydro-2 # -l-benzopyran-3-yl] -4-N, N-diethylaminobenzamide; (S) -N- [5 (4-Methylpiperazin-1-yl) -3,4-dihydro-2-yl -benzopyran-3-yl] -4-trifluoromethoxybenzamide; (S) -N- [5 (4-Methylpiperazin-1-yl) -3,4-dihydro-2-yl-1-benzopyran-3-yl] -4- ( 4-piperidon-1-yl) benzamide; (S) -N- [5 (4-Methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (hexahydro- 1, 4-diazepin-5-on-l-yl) benzamide, or (S) -N- [5 (4-Methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl ] -4- (4-benzylpiperazin-1-yl) benzamide in the form of a free base or a pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical formulation characterized in that it comprises as an active ingredient a therapeutically effective amount of the compound according to any one of claims 1 to 11, as an enantiomer or racemate in the form of a pharmaceutically acceptable free base or salt or solvate, same, optionally in association with diluents, excipients, or inert carriers.

13. A pharmaceutical formulation according to claim 12, characterized in that it is for use in the treatment of disorders mediated by 5-hydroxytryptamine.

14. A pharmaceutical formulation according to claims 12 or 13, characterized in that it is for use in the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism , tobacco abuse, autism, attention deficit disorder, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain, hypertension, urinary incontinence or vasospasm; or for the control of tumor growth.

15. A compound according to the definition of claims 1 to 11, characterized in that it is used in therapy.

16. A compound according to the definition of claim 15, characterized in that it is for use in the treatment of disorders in the central nervous system.

17. A compound according to the definition of claim 16, characterized in that it is for use in the treatment of disorders in mood, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism , tobacco abuse, autism, deficiency in attention, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension.

18. A compound according to the definition of claim 15, characterized in that it is for use in the treatment of urinary incontinence or vasospasm, or for the control of tumor growth.

19. A compound according to the definition of claim 15, characterized in that it is for use in the treatment of disorders mediated by 5-hydroxytryptamine.

20. A compound according to the definition of claim 19, characterized in that it is for use as an antagonist of h5-HT? B.

21. The use of a compound defined in any of claims 1 to 11, in the manufacture of a medicament for the treatment of disorders in the central nervous system and / or of urinary incontinence or vasospasm; or for the control of tumor growth.

22. The use according to claim 21, in the manufacture of a medicament for the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, abuse of the tobacco, autism, attention deficiency, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension.

23. The use of a compound according to the definition of any one of claims 1 to 11, in the manufacture of a medicament for the treatment of disorders mediated by 5-hydroxytryptamine.

24. The use according to claim 23, wherein the compound according to any one of claims 1 to 11 is used as an antagonist of h5-HT? B.

25. A method for the treatment of disorders in the central nervous system and / or urinary incontinence or vasospasm, or for the control of tumor growth, characterized in that it is carried out by administration to a mammal, including man, that needs this treatment, of a therapeutically effective amount of a compound defined in any one of claims 1 to 11.

26. A method according to claim 25, characterized in that it is for the treatment of disorders in the state of mind, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism , deficiency in attention, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension.

27. A method for the treatment of a disorder mediated by 5-hydroxytryptamine, characterized in that it is carried out by administration to a mammal, including man, in need of such treatment, of a therapeutically effective amount of a compound defined in accordance with any of claims 1 to 11.

28. A method according to claim 18, characterized in that the compound according to any one of claims 1 to 11 is used as an antagonist of h5-HT_B.

29. A process for the preparation of the compound of formula I according to claim 1, characterized in that it is carried out by the following steps A (i) acylation, in the case when R_ is alkyl of 1 to 6 carbon atoms or cycloalkyl - of 3 to 6 carbon atoms, Y is NR2CO, R2 is hydrogen and X and R3 are as defined in general formula I in claim 1, of a compound of formula A, (A) (I) with an activated carboxylic acid R3-C0Lg? wherein Lgi is a leaving group or by the use of a carboxylic acid R3-C00H with an activation reagent; A (ii) acylation, in the case when Ri is hydrogen, Y is NR2CO, R2 is hydrogen, Rc is a protecting group and X and R3 are as defined in general formula I in claim 1, a compound of the Formula B, (B) (I) with an activated carboxylic acid R3-COLg? wherein Lg_ is a leaving group or by the use of a carboxylic acid R3-COOH with an activation reagent, followed by removal of the Rc protecting group; A (iii) debenzylation, in the case when Ri is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, X and R2 are as defined in general formula I above and R9 shown below, is alkyl from 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2) m0H wherein m is a number of 2 to 6 or COR8, of a compound of formula la, followed by a) hydrogenation, b) alkylation , c) alkylation and removal of a protective group or d) acylation (the I) B (i) reacting, in the case when R_ is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, Y is CONR2, X and R2 and R3 are as defined in general formula I above , an activated carboxylic acid, of a compound of formula C; (C) (I) with an aniline or amine HNR2R3; or B (ii) reacting, in the case when Ri is hydrogen, Y is NR2CO, Rc is a protecting group and X, R2 and R3 are as defined in general formula I above, an activated carboxylic acid, of a compound of formula D; (GAVE) with an aniline or amine HNR2R3, followed by removal of the protective group Rc. the reaction, in the case when R_ is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, Y is NR2C0NR2, R2 is hydrogen and X and R3 are as defined in general formula I above, a composed of formula A, (A) (Or with an azide, suitable, in the presence of the carboxylic acid R3-COOH.

30. A compound characterized in that it has the formula wherein X = N or CH Z = NH2 or COOH; Ri is H, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms. DERIVATIVES SUBSTITUTED FROM C3OMANO SUMMARY OF THE INVENTION The present invention relates to novel compounds derived from dihydro-2H-1-benzopyran substituted with piperidyl or piperazinyl, having the formula (1) wherein X is N or CH; Y is NR2CH2, CH2NR2, NR2CO, CONR2, NR2S02 wherein R2 is H or alkyl of 1 to 6 carbon atoms; Ri is H, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; R3 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms 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 can be monosubstituted or disubstituted with R 4 and / or R 5; and n is a number from 0 to 4; as enantiomers- (R), enantiomers- (S) or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof, to a process for their preparation, to pharmaceutical compositions containing the therapeutically active compounds and to the use of those active compounds.