MXPA01005232A - Benzofuran derivatives, their preparation and use - Google Patents

Abstract

The present invention relates to benzofuran derivatives having general Formula (I). A is selected from (1), (2), (3), (4) wherein:Z is O or S;s is 0 or 1;q is 0 or 1;R4 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl-Aryl, or C1-6-alkyl-O-Aryl;D is a spacer group selected from branched or straight chain C1-6-alkylene, C2-6-alkenylene and C2-6-alkynylene;its enantiomers, and pharmaceutically acceptable acid addition salt thereof. The compounds are potently binding to the 5-HT1A receptor.

Description

DERIVATIVES OF BENZOFURANO, ITS PREPARATION AND USE The present invention relates to novel benzofuran derivatives that bind potently to the 5-HT? A receptor, to pharmaceutical compositions containing these compounds and to the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent inhibitors of serotonin reuptake, and are considered particularly useful for the treatment of depression.

Prior Art Clinical studies of known 5-HT1A partial agonists, such as buspirone, ipsapirone and gepirone, have shown that partial 5-HT? A agonists are useful in the treatment of anxiety disorders such as anxiety disorder. generalized, panic disorder-, and obsessive compulsive disorder (Glitz, DA, Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that total agonists are also useful in the treatment of disorders related to the anxiety mentioned above (Schipper, Human Psychopharm., 1991, 6, S53). In addition, there is evidence, both clinical and preclinical, that supports a beneficial effect of partial 5-HT.A agonists in the treatment of depression, as well as disorders of impulse control and hol abuse (van Hest, Psychopharm., 1992). , 107, 474; Schipper et al., Human Psychopharm., 1991, 6, S53; Cervo et al., Eur. J. Pharm., 1988, 158, 53; Glitz, DA, Pohl, R., Drugs 1991, 41, 11; Grof et al., Int. Clin Psychopharmacol, 1993, 8, 167-172; Ansseau et al., Human Pspharmacology, 1993, 8, 279-283). The partial agonists and agonists of 5- HTIA inhibit the insult induced by isolation in male mice, indicating that these compounds are in the treatment of aggression- (Sánchez et al., Psychopharmacology, 1993, 110. 53-59). In addition, 5-HTIA agonists have been reported to show activity in animal models that predict antipsychotic effects (Wadenberg and Ahlenius J. Neural, Transm., 1991, 83, 43, Ahlenius, Pharmacol. &Toxicol., 1989, 64 , 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med.

Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052) and therefore may be useful in the treatment of psychotic disorders such as schizophrenia. Recent studies also indicate that 5-HT? A receptors are important in the serotonin modulation of haloperidol-induced catalepsy (Hic s, Life Science 1990. 47, 1609), suggesting that 5-HT agonists are useful in the treatment of side effects induced by antipsychotic agents with encionales such as for example haloperidol. 5-HT ?A agonists have demonstrated neuroprotective properties in rodent models of global and focal cerebral ischemia, and therefore may be useful in the treatment of ischemic disease states (Prehn, Eur. J. Pharm., 1991, 203, 213). Pharmacological studies have been presented indicating that 5-HTJA antagonists are useful in the treatment of senile dementia (Bowen et al., Trends Neur. Sci. 1992, 15, 84). Schechter et al., Serotonin, 1997, Vol. 2, Edition 7, presents a review of 5-HTIA antagonists and potential therapeutic targets proposed for these antagonists, based on the information preclinical and clinical. It is established that 5-HT 1A antagonists may be useful in the treatment of schizophrenia, dementia associated with Alzheimer's disease and in combination with SSRI antiretrovirals also useful in the treatment of depression. Both in animal models and in clinical trials it has been shown that 5-H agonists IA exert an an ihipertive effects by means of a central mechanism (Saxena and Villalon, Trends Pharm, Sci. 1990. 11, 95 Gilí is and others, J. Pharm, Exp. Ther, 1989, 248, 851). Therefore, the ligands of 5-lHT? A may be beneficial in the treatment of cardiovascular disorders. Inhibitors of 5-HT reabsorption are well-known antidepressant drugs, and are useful for the treatment of panic disorders and social phobia. The effect of the combined administration of a compound that inhibits the reuptake of serotonin and a 5-HT 1A receptor antagonist has been evaluated in several studies (Innis, RB et al., Eur. J. Pharmacol., 1987, 143, p. 195-204 and Gartside, SEJ Pharmacol., 1995, 115, p.1064-1070, Blier, P. et al. To Trends Pharmacol., Sci. 1994, 15, 220). In these studies it was found that antagonists of 5-HT1A receptors would annul the initial disruption in the neuro-tussans of 5-HT induced by serotonin reuptake inhibitors, and thus produce an immediate reinforcement of 5-HT transmission. and a quicker start of the therapeutic action. Several patent applications covering the use of a combination of a 5-HT ?A antagonist and a serotonin reuptake inhibitor have been filed for the treatment of depression (see EP-A2-687 472 and EP-A2- 714 663). Accordingly, it is believed that agents that act on the 5-HT receptor, both agonists and antagonists, are of potential use in the therapy of psychiatric and neurological disorders, and are therefore highly desired. In addition, antagonists which at the same time have potent serotonin reuptake inhibition activity may be useful for the treatment of depression.

Brief Description of the Invention It has now been discovered that the compounds of a certain class of benzofuran derivatives are bind to the 5-HT1A receptor with high affinities. In addition, it has been found that many of these compounds possess potent serotonin reuptake inhibition activity. Therefore, the present invention relates to new compounds of general Formula I: wherein R1 is hydrogen, halogen, trifluoromethyl, tif luor ome ti 1 s ul f oni 1 ox i, C - alquilo alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_8 cycloalkyl C - - alco alkoxy, hydroxy, formyl , acyl, amino, C? _6 alkylamino, C2-? 2 dialkylamino, acylamino, C? -6 alkoxycarbonylamino, aminocarbonylamino, a 1 qui 1 ami noca rboni 1 ami no of C? -6, di a 1 qu i 1 aminoca rboni 1 amino of C2-? 2. nitro, cyano, COOH, or COO-C 1-6 alkyl; R 'and R- on each independently selected from hydrogen, trifluoromethyl, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_s cycloalkyl and C i_6 alkoxy; n is 1,2,3,4 or 5; m is O or 1; A is selected from the following groups: where Z e s 0 or S; s e 0 or 1; which is O or l; R4 is hydrogen, -alkyl, C2_e alkenyl, C2_e alkynyl. C? -6-Aryl alkyl, or C? _? -Ar alkyl, or D, is a spacer group selected from the straight or branched chain of C? -6 alkylene and C2-6 alkenylene. C2_6 alkynylene; B is a group selected from a group of formula (II), (III) and (IV) (III) (IV) wherein R5, R6, R7, R8, R9 and R10 are each independently selected from the substituents R1; or R8 and R9 together form a ring of 5 or 6 fused members that optionally contain other heteroatoms; or two of the groups of R5, R6 and R7 are joined together forming a bridge t e-0- (CH) p-0-, where p is 1 or 2; Ar and Aryl are independently selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidi 1, 1-indolyl, 2-indolyl 3-indolyl, i ndo 1 -2 - on- 1 - i 1 o, i ndo 1 - 2 - on- 3 - i 1 o, 2- or 3 -benz of uran i 1, 2 or 3 -ben zo ti or phenyl , 1-naphthyl or 2-naphthyl, each optionally substituted with halogen, C? _6 alkyl,? -, C? _6 alkyl, hydroxy, C-alkylsulfonyl? - ß, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, cycloalkyl of C3-a. C3_8-alkyl-cycloalkyl C? -6. nitro, amino, C? -6 alkylamino, C2_? 2 dialkylamino, acylamino or alkylenedioxy; their enantiomers and pharmaceutically acceptable acid addition salt thereof. In one embodiment of the invention A is a group of the formula (1) and the other substituents are as defined above. In another embodiment of the invention, A is a group of the formula (2) and the other substituents are as defined above. In another embodiment of the invention, A is a group of the formula (3) and the other substituents are as defined above. In another embodiment of the invention, A is a group of the formula (4) and the other substituents are as defined above. Therefore, in a preferred embodiment of the invention A is a group of the formula (1) and R4 is methyl, ethyl, propyl, pr op-2-en-1-yl or, 2-furylmethyl, or 2- phenoxyethyl; q = 0; or A is a group of the formula (1) and Z is 0, and the other substituents are as defined above. In another embodiment of the invention, B is a group of the formula (II). preferably a phenyl to the oxygenated, a group b in z or di ox a, or a group 1, 2 -me ti 1 endi oxybenzene, and the other substituents are as defined above In another embodiment of the invention, B is a group of the formula (III), preferably a 3-indolyl group, and the other substituents they are as defined above. In another embodiment of the invention, B is a group of the formula (III), preferably a 3-indolyl group, and the substituents R8 and R9 preferably selected from hydrogen, methyl, fluoro, chloro, bromo, iodo, t-butyl or i-propyl at position 5; or fluoro, chloro or carboxy in the 7-position; or 5,7-difluoro-4-fluoro-7-methyl, or 4-chloro-7-methyl; or the two substituents together form a pyridyl ring fused to the 3-indo lyl. In another embodiment of the invention, B is a group of the formula (IV), other substituents are as defined above. Preferably ar is phenyl or halogen substituted with halogen or CF3, most preferably substituted with F or Cl in the 4 position, or Cl or CF3 in the 3-position. R1 is preferably H, CN or F in the 5-position of the group is ob in zofuran.

R2 and R3 are preferably selected from hydrogen or methyl. preferably is 2, 3 or 4. m is preferably 0. In a preferred embodiment of the invention, n = R 'and R- are both hydrogen; R1 is H, CN or F at position 5 of the isobenzofuran group; and Ar is phenyl, which can be substituted with F or Cl at the 4-position or with Cl or CF3 at the 3-position, and the other substituents are as defined above. In another preferred embodiment of the invention, A is a group of the formula (1); q = 0; R4 is methyl; D is propylene; m = 0; and B is a 1,4-benz odi-oxano group of Formula (II) attached in the 5-position, and the other substituents are as defined above. In another preferred embodiment of the invention, A is a group of the formula (1); R 4 is CH 3 or prop-2-en-1-yl; n = 3; D is ethylene or propylene; and B is a phenyl group wherein at least one substituent is OMe and the other substituents s s ~ n as defined above. In another embodiment of the invention, A is a group of the formula (1); q is 0; R4 is methyl, ethyl, propyl, 2-p r open-1-i 1 o, 2-fur i lme t i 1 o or 2-phenoxyethyl; D is ethylene, propylene or butylene; m is 0; and B is a 3-indolyl group of Formula (III), and the other substituents are as defined above. In another preferred embodiment of the invention, A is a group of the formula (2) or (3); n = 3; m = 0; and B is a 4- or 5-indolyl group of the Formula (IV), wherein R 10 is hydrogen; R1 is CN at position 5 of the s s or e n z or f u r a n and Ar is 4-Fluor or feni 1 o, and the other substituents are as defined above. The invention further relates to a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or diluent. In another embodiment, the invention relates to the use of a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of a disorder or disease that responds to the effect of 5-HT1A receptors.

In particular, the invention relates to the use of a compound according to the invention, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of depression, psychosis, anxiety disorders, disorder of panic, obsessive compulsive disorder, impulse control disorder, alcohol abuse, ischemia aggression, senile dementia, cardiovascular disorders or social phobia. In yet another embodiment, the present invention relates to a method for the treatment of a disorder or disease of the body of a living animal, including a human, that responds to the effect of 5-HT? A receptors which comprises administering said body. of living animal, including human, a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof. The compounds of the invention have high affinity for the 5-HT? A receptor. Accordingly, the compounds of the invention are considered useful in the treatment of depression, psychosis, anxiety disorders, such as generalized anxiety disorder, panic disorder and obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischemia, senile dementia, cardiovascular disorders and social phobia. Due to their combined antagonism of 5-HT-A receptors and the serotonin reuptake inhibitor, many of the compounds of the invention are considered particularly useful as fast-acting drugs for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.

Detailed Description of the Invention Some of the compounds of general Formula I may exist as optical isomers thereof, and said optical isomers are also encompassed by the invention. The term "C? _6 alkyl" refers to a branched or unbranched alkyl group, having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl , 2 -me ti 1 - 2 -pr op i 1 o and 2 -me ti 1 - 1 -pr op i 1 o.

Also, C2_6 alkenyl and C2_6 alkynyl. respectively, they designate said groups having from two to six carbon atoms, inclusive. Halogen means fluoro, chloro, bromo or iodo. The term cycloalkyl of C3-s designates a monocyclic or bicyclic carbocycle having three to eight C atoms, such as cyclopropyl, cyclopentyl, cyclohexyl cycloheptyl and cyclooctyl. The terms "C6-6 alkoxy, C6-6 alkylthio, C6-6 alkylsulfonyl". designate said groups in which the alkyl group is C 1 to 6 alkyl as defined above. Acyl means -CO-alkyl, wherein the alkyl group is C? _6 alkyl as defined above. Alkylamino of C? _e means -NH-alkyl, and dialkylamino of C2_ 2 signifies -N- (alkyl) 2, where the alkyl group is a C-6 alkyl as defined above. Acylamino means -NH-acyl, wherein acyl is as defined above.

C 1 -C 6 alkoxycarbonylamino means 1 to 1 or -O-CO-NH- where the alkyl group is a C 6 alkyl as defined above. To the one which laminoca rboni lamí of C? -6 means to 1 qui 1 or -NH - CO-NH - where the alkyl group is C? E alkyl as defined above. Say to 1 qui 1 amino ca rboni 1 ami no of C2-? 2 signifies (a 1 qu i 1 o) 2 -N- CO-NH - where the alkyl group is C? _6 alkyl as defined above. Examples of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, succinic ascorbic, oxalic, bis-methyl 1 -alkyl, methanesulfonic, and anhydrous acids, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic "glycolic, p-aminobenzoic, glutamic, benzene sulphonic and acetic acid theophylline, as well as the 8 -ha 1 ot eo f ilina s, for example, 8-br orno teofi 1 ina.Examples of addition salts of inorganic acids according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic acids, phosphoric and nitric acid addition salts of the invention with preference they are pharmaceutically acceptable salts formed with non-toxic acids. In addition, the compounds of this invention can exist in non-soluble form as well as in soluble form with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, soluble forms are considered equivalent to non-soluble forms for the purposes of this invention. Some of the compounds of the present invention contain chiral centers, and said compounds exist in the form of isomers (e.g. enantiomers). The invention includes all the isomers? any mixture thereof, including racemic mixtures. The racemic forms can be resolved at the optical antipodes by known methods, for example, by separating their salts with energetic salts thereof with an optically active acid, and releasing the optically active amino compound by treatment with a base. Another method for resolving racemates in the optical antipodes is based on chromatography in an optically active matrix. The racemic compounds of the present invention can thus be resolved in their optical antipodes, by example, by fractional crystallization of salts d- or 1 - (t a r t ra t os, mandelatos, or camphor sulphonate) for example. The compounds of the present invention can also be resolved by means of the formation of di- or t-orne derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, can be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiaoners Racemates, and Resolutions," John Wiley and Sons, New York (1981). In addition, optically active compounds can be prepared from optically active starting materials. The compounds of the invention can be prepared by one of the following methods which they comprise: a) alkylating an amine of the Formula (V) wherein R1, R2, R, R4, n and Ar are as defined above, with an alkylating agent of the formula G- (D) s - (Z) q- (CH2) m- B, wherein D, Z, m, s, q are as defined above, and G is a suitable leaving group, such as halogen, mesylate or toslate; b) alkylating an amine of the formula H-A- (CH2) mB wherein A, m and B are as defined above, with an alkylating agent of the formula wherein R1, R2, R3, n and Ar are as defined above and G is compatible with the releasing group such as halogen, mesylate, or tosylate. c) reductive alkylation of an amine of the formula wherein R1, R2, R3, R4, n and Ar are as defined above, with an aldehyde of the formula (VIII) where Z, m, q and B are as defined above, and t is 1-5; d) reduce an amide of the formula (XI) wherein R1, R2, R3, R4, n, q, Ar, Z, m and B are as defined above, and t is 1-5; e) release final product by means of Hofmann elimination, from resin of the f or rmu 1 a (xp) wherein R1, R2, R3, R4, n, s, q, Ar, D, Z, m and B are as defined above, G is as defined above; and HOR 'is a substituted hydroxy resin such as crosslinked hydroxymethylpyrolid or Wang resin. f) reacting a compound of the f or rmu l a XII! wherein R1, R2, R3, R4, Ar, D and N are as defined above, (OH) 2Q is a diol such as pro-glycol or substituted ethylene glycol, or a diol linked to a polymer, with a hydrazine of the or rmul a XIV wherein R and R are as defined above, using Lewis acids as the catalyst.

The alkylations according to Methods a and b are generally effected by boiling the reagents under reflux, or by heating them to a fixed temperature in a suitable solvent, such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl, N, N-dimethylformamide, dimethyl sulfoxide or l-methyl-2-pyrridinone, in the presence of a base such as triethylamine or potassium carbonate. Amines of formula V are prepared by means of demethylation according to the method described by Bigler et al., Eur. J. I Chem. Chim. Ther., 1977, 12, 289-295, or by the methods detailed in Examples 14 and 15. The starting materials used in Example 14 were prepared as described in Example 9, or from readily available compounds, by standard methods. The enantiomers of 1 - [3 - (dime ti 1 amino) r op i 1] - 1 - (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile used as starting material for the demethylation are prepared as described in EP Patent No. 347066. Alkylating agents of the formula G- (D) s- (Z) q- (CH 2) m-B are commercially available, are prepared by obvious methods to the chemist skilled in the art or are prepare as exemplified in Examples 5-8. Ethyl 1, -ben z odi oxan-5-caboxylate used as starting material in Example 5 is prepared by obvious methods for the chemist skilled in the art, from the corresponding carboxylic acid prepared according to the literature ( Fuson and others, J. Org. Chem., 1948, 13, 489). The alkylating agents of formula VI are prepared from the corresponding dimethylamine (Formula VI: G = N (Me) 2) as exemplified in "Example 9. Secondary amines of the formula HA-CH2 can be obtained commercially , prepared by obvious methods to the chemist skilled in the art, or can be prepared according to literature procedures 1 - (2-methoxymethyl) 1) piperazine prepared according to Pollard et al, J. Org. Chem ., 1958, 23,1333. [2 - (2 -Me t-oxy-enoxi) eti 1] me thi lamina and [2- (3-me t ox if enox i) eti 1] -me ti 1 ami na se They prepare, as exemplified in Examples 7 and 10. Using 2-me t ox ox et enox ia cé ti co acid 3-me t oxi f enoxi a cé ti co commercially available, respectively, as starting materials. According to the method c and d are carried out according to the methods of the standard literature, using NaCNBH3, NaBH4 or NaBH (OAc) 3 as a reducing agent in a suitasolvent. The reductions according to Methods e and f are generally effected by the use of LIAH4, AIH3 or diborane in an inert solvent, such as tetrahydrofuran, dioxane, or diethyl ether, at room temperature or at a slightly 1-evade temperature. The release of final products by Hofmann elimination in Method g is generally effected by the use of an organic base such as triethylamine or diisop opylethylamine, in an aprotic organic solvent, such as dichloromethane, toluene or N, N-dimethylformamide. The polymer of formula XII is prepared in a synthesis sequence as exemplified in Example 4 and as described below. The initial acrylic ester resin (CH2CHC (0) OR ') prepared according to literature procedures (Brown et al., J. Chem. Soc., 1997, 119, 3288-95), by acylation of commercially availasubstituted hydroxy resins, such as crosslinking of hi dr oxime t ilpo 1 iestir eno or Wang resin, with acryloyl chloride. The secondary amines of the formula H2N-D-Z- (CH2) m-B are introduced by addition of Michael in an organic solvent such as N, N-dimethylformamide, at room temperature. The secondary amines used or can be obtained commercially, obvious methods can be prepared for the chemist skilled in the art, or they can be prepared according to literature procedures. 3 - (2-Me t oxi f eni 1) pr op i lamina prepared according to Leeson et al., J. Med. Chem. 1988, 31, 37-54, 3 - (3-me t oxy 1) pr op i 1 ami na according to Meise and others. Liebigs Ann. Chem., 1987 639-42, 3- (2-methoxy phenoxy) propy1 amine according to Augsein et al., J. Med. Chem., 1965, 8, 356-67, 3- (3-me t oxi phenoxy) prop i 1 amine according to Bremner et al., Aust. J. Chem. 1984, 37, 129-41, 2-ben ci loxie t i 1 ami na agree Harder et al., Chem. Ber. 1964, 97, 510-19, 2- (1H-indolyl-3-yl) ethylamine according to Nenitzescu et al., Chem. Ber. , 1958, 91, 1141-45 and 3- (lH-indo il) pr op i 1 ami na, according to Jackson et al., J. Am. Chem. Soc., 1930. 5029. The second diversifying group is introduced by means of alkylation an agent of formula VI, causing the reagents to boil under reflux, or by heating them to a temperature set in a suitasolvent, such as tetrahydrofuran. of or uro, dioxane, ethanol, 2-propanol, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide or l-methyl-2-pyrroneidinone, in the presence of a solubase such as diisopropylethylamine or triethylamine, or by means of reductive alkylation with aldehyde of formula IX, using standard phase synthesis literature methods, using NaCNBH3, NaBH4 or NaBH (OAc) 3 as reductive agent a suitasolvent. The third diversifying group was introduced by measuring quaternization, using an alkylating agent of the formula R 4 -G in an organic solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, dimethyl acetate, dimethyl sulfoxide, or 1 -me i 1- 2 - pyro 1 i dinsna, at room temperature, giving resins of the formula XII. The indole formation according to the method h is carried out by means of the reaction of acetals of the formula XIII with aryl hydrazines of the formula XIV producing the corresponding t hydrazones, which are subsequently converted into Índoles by means of the synthesis of indole Fischer.

The CGU of synthesis is preferably carried out as a procedure, using acid catalysts Lewis, preferably zinc chloride or boron fluoride, or protic acids, preferably acid sulfuric acid or phosphoric acid, in a suitasolvent such as acetic acid or ethanol, at an elevated temperature, acetals of the formula XIII are prepared by alkylation of secondary amines formula V with acetals of the formula XV.

XV using the conditions described above for methods a and b. Alternatively, the acetals of formula XIII are prepared by alkylation of acetals of formula XVI XVI with an alkylating agent of formula VI using the conditions described above of methods a and b. Acetals of formula XVI are prepared by reaction of acetals of formula XV with primary amines of formula NH2R4 using standard conditions. Acétals linked to polymers of the formula XV are prepared by reaction of aldehydes of the formula GB-CH2-CHO with 2, 2-dimime ti 1 -1,3-di oxol an-4-i 1 -me t sxime ti 1 polystyrene commercially available, in a suitable solvent such as toluene, using p-t acid Ol uens ul foni co as a catalyst, at elevated temperature. 4 - C 1 or obu t ana 1, 5 - c 1 or r open t ana 1 and 6 - c 1 or ohexana 1 were prepared analogously to the method described by Normant et al., Tetrahedron 1994 50 (40), 11665.

Examples The melting points were determined on a Büchi SMP-20 apparatus. and they are corrected. The table spectra were obtained in a Quattro system, MS-MS, from VG Biotech, Fisons Instruments. The MS-MS system was connected to the HP 1050 modular HPLC system. A volume of 20-50 μl of the sample (10 μl / mL) dissolved in a mixture of 1% acetic acid in acetonitrile / water 1: 1 was introduced by means of the samplings at a flow of 30 μl / min inside the Electrospray Source. Spectra were obtained at two standard establishments operating conditions. The analytical LC-MS data were obtained in the PE Sciex API 150EX instrument, equipped with the lonSpray source and the Shimadzu LC-8 A / S LC-10A LC system. The conditions of LC (50 X 4.6 mm YMC ODS-A with particles of size 5 μm) were linear gradient elution with water / acetonitrile / trifluoroacetic acid (90: 10: 0.05) to water / acetonitrile / trifluoroacetic acid (10:90 : 0.03) in 7 min at 2 mL / min. The purity of integration of the UV trace (254 nm) was determined. The retention times Rt is expressed in minutes. One establishment to obtain molecular weight information (MH + eV) and the other establishment to induce fragmentation patterns (70 eV) deduced the basic information. The relative intensities of the ions were obtained from the fragmentation pattern. When no intensity is indicated for the Molecular Ion (MH +), this ion was only present under the first setting of operating conditions. The LC -MS - s preparatory process was carried out by the same instrument. The LC conditions (50 X 20 mm YMC ODS-A with a 5 μm particle size) were linear gradient elution with water / acetonitrile / trifluoroacetic acid (80: 20: 0.05) to water / acetonitrile / trifluoroacetic acid (10: 90: 0.03) in 7 min at 22.7 mL / min. The collection of the fraction was effected by EM detection of divided flow.

The NMR spectra were recorded at 500.13 MHz, on a Bruker Avance DRX500 instrument, or at 250.13 MHz on a Bruker AC 250 instrument, using deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D), solvents were used. used TMS as an internal reference standard.Change change valves are expressed in ppm valves.The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet t = triplet, q = quartet, qu i = quin tete, h = heptete, dd = double doublet, dt = donle triplet, dq = double cuartete, tt = triplet of triplets, m = mul tiple te.The NMR signals corresponding to acidic protons are generally omitted. Water in crystalline compounds was determined by Karl Fischer titration.The standard working procedures refer to the extraction of indicated organic solvent from appropriate aqueous solutions, the drying of the combined organic extracts (anhydrous MgSO4 or Na2SO4), fil by bringing and evaporating the solvent i n va c u o. Silica gel of the Kieselgel 60 type was used for column chromatography. ASTM 230-400 mesh network.

Example 1 (+) -1- [3- [[4- (1,4-Benzodioxan-5-yl) butyl] -methylamino] propyl] -1- (4-f luorofenyl) -1,3-dihydro- i s obenz of uran - 5 - ca rboni trilo (la). A mixture of 5- (4-bromobutyl) -1, 4-benzodioxane (1.5 g, 5.5 mmol), (+) -1- [3- (methylamino) propyl] -1- (4-fluorophenyl) -1,3 -di hi dr ois ob enzofur an - 5 - ca rb on itri 1 o (2.2 g, 5.5 mmol), potassium carbonate (3.0 g, 22 mmol) and methyl isobutyl ketone (150 mL) were boiled under reflux for 16 hours. After cooling to room temperature, the organic phase was washed with water (150 mL), the solvents were evaporated in vacuo and the remaining oil was purified by column chromatography (ethyl acetate / heptane / trieti 1 ami no 75). : 20: 5), achieving 2.0 g (73%) of the title compound as an oil [] 22D + 8.93 ° (c 0.5; CH30H). XH NMR (CDC13) d 1.25-1.35 (m, 1H), 1.40-1.60 (m, 5H), 205-2.30 (m, 9H), 2.55 (t, 2H), 4.20-4.30 (m, 4H), 5.10 -5.20 (m, 2H), 6.65-6.75 (m, 3H), 7.00 (t, 2H), 7.35 (d, 1H), 7.40 (dd, 2H), 7.50 (s, 1H), 7.60 (d, 1) H); MS m / z 501 (MH +, 100), 262 (27), 149 (77), 109 (52). The following compounds were prepared analogously: (+) -1- [3- [[3- (1,4-Benzodioxan-5-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ax a 1 ato (1b): pf. 114-16 ° C (ethyl acetate); [] 22D + 8.96 ° (c 1.0; CH30H). XH NMR (DMSO-d6) d 1.35-1.45 (m, 1.45-1.55 (m, 1H), 1.80 (m, 2H), 2.20-2.30 (m, 2H), 2.45-2.55 (m, 2H), 2.60 ( s, 3H), 2.90 (, 2H), 2.95 (m, 2H), 4.20-4.30 (m, 4H), 5.20 (m, 2H), 6.65-6.75 (m, 3H), 7.10-7.20 (m, 2H) ), 7.55-7.60 (m, 2H), 7.70-7.80 (m, 1H), 7.80 7.95 (m, 2H), MS m / z 488 (MH +, 100), 262 (33), 149 (52), 109 (55) 1- [3- [[2- (1,4-Benzodioxan-5-yl) ethyl] methyl-amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-fura n - 5 - charcoal itri 1 or oxalate (le): mp 118-20 ° C (ethyl acetate); 1 H NMR (DMSO- 6) d 1.40-1.70 (m, 2H), 2.25 (t, 2H), 2.70 (s, 3H), 2.75-290 (m, 2H), 2.90-3.15 (m, 4H), 4.15-4.30 (m, 4H), 5.20 (m, 2H), 6.65-6.80 (m, 3H) 7.20 ( t, 2H), 7.60 (dd, 2H), 7.70-7.85 (m, 3 H); MS m / z 473 (MH +, 64), 323 (13), 262 (24), 163 (100), 109 (25). 1 ~ [3- [[1,4-Benzodioxan-5-ylmethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-f ur an-5-ca rb on itri 1 or oxalate (Id): mp 160-62 ° C (acetone / methanol); XH NMR (DMSO-d6) d 1.40-1.70 (m, 2H), 2.25 (t, 2H), 2.60 (s, 3H), 2.90 (t, 2H), 4.00 (s, 2H), 4.20-4.30 (m, 4H), 5.20 m. 2H 6.80-7.00 m, 3H), 7.15 (t, 2H), 7.50-7.65 (dd, 2H), 7.70-7.85 m, 3H); MS m / z 459 (MH +, 7), 109 (100).

Example 2 1- (4-Fluorophenyl) -1- [3- [4- (2-methoxyphenyl) -piperazinyl] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (2a). A mixture of 1 - (3-c 1 or op r op i 1 1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-ca rboni thyl (2.5 mmol is), 2-methoxyphenyl) piperazine (2.0 g, 10.4 mmoles), potassium carbonate (3 g, 22 mmol) and methyl isobutyl ketone (200 L) was bubbled under reflux for 16 hours. After cooling to room temperature, the organic phase was washed with water (200 mL), the solvents were evaporated in vacuo and the remaining oil was purified by column chromatography (ethyl acetate). 1 amine 75: 20: 5) the title compound was crystallized from diethyl ether 1.5 g (40%): mp. 147-49 ° C; 1R NMR (DMSO-d6) d 1.30-1.65 (m, 2H), 2.10-2.30 (m, 2H), 2.40 (t, 2H), 2.50-2.70 (m, 4H), 2.90-3.20 (m, 4H), 3.85 (s, 3H), 5.20 (m, 2H), 6.70-7.10 (m, 6H), 7.30-7.55 (m, 4H), 7.60 (d, 1H); MS m / z 472 (MH +, 100), 26 ~ 2 109 (19).

The following compounds were prepared analogously: 1- (4-Fluorofenyl) -1- [3- [[2- (2-methoxyphenoxy) -ethyl] methylamino] propyl] -1, 3 -dihi dr oi s oben zof ur an- 5-carboni tri 1 or (2b): (oil) XH NMR (CDC13) d 1.30-1.40 (m, 1H), 1.40-1.55 (m, 1H), 2.10-2.20 (m, 2H), 2.25 (s, 3H), 2.40-2.45 (t, 2H), 270-2.80 (m, 2H), 3.70 (s, 3H), 4.05 (t, 2H), 5.15 (m, 2H), 6.85-7.00 (m, 6H), 7.30-7.45 (m, 3H), 7.50 (s, 1H), 7.55 (d, 1H). 1- (4-Fluorophenyl) -1- [3- [[2- (3-methoxyphenoxy) -ethyl] methylamino] propyl] -1, 3 -di hi dr oi s sben zof uran - 5 - ca rbon iti 1 o (2c): (oil) -i NMR (CDCI3) d 1.30-1.40 (m, 1H), 1.40-1.55 (m, 1H), 2.10-2.20 (m, 2H), 2.25 (s, 3H), 2.40 ( t, 2H), 2.70-275 (m, 2H), 3.70 (s, 3H), 4.00 (t, 2H), 5.15 (m, 2H), 6.40-6.55 (m, 3H), 7.00 (t, 2H), 7.20 (t, 1H), 7.35 (d, 1H), 7.40 (dd, 2H), 7.50 (s, 1H), 7.55 (d, 1H). (S) -l- [3 - [[4- (12_-Indol-3-yl) butyl] methyl-amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5-carboni trill (2d): LC / MS (m / z) 482 (MH +), Rt = 4.24 and purity: 84%. 1- [3- [[4- (lJ? -Indol-3-yl) butyl] methylamino] -pr op i 1] - 1 - f in i 1 - 1.3 -dihydr oi s oben zof ur ano (2e): LCMS (m / z) 439 (MH +), Rt = 4.33, purity: 77%. (5) -1- [3- [[3- (L-Indol-3-yl) propyl] methyl-amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5- carbonyl trile (2 f): LC / MS (m / z) 468 (MH +), Rt = 4.11 purity: > 99% 1 - [3 - [[3- (l, l-lol-3-yl) propyl] methylamino] -pr opi 1] - 1 - f eni 1 - 1, 3 -dihi dr oi s oben zof ur ano (29): LC / MS (m / z) 425 (MH +), Rt = 4.15, purity: >; 99. 5- [3- [[3- (1-Phenyl-1, 3-dihydroisobenzofuran-1-y1) pr op i 1] me ti 1 amino] pr opi 1] - 1 -ben z odi oxano (2h ): LC / MS (m / z) 444 (MH +), Rt = 4.12, purity: 97%. 5- [3- [[3- [1- (3-Chlorophenyl) -1,3-dihydroiso-benzofuran-1-yl] propyl] methylamino] propyl] -1,4-benzodioxane (2i): LC / MS ( m / z) 478 (MH +), Rt = 4.45. purity: 93%. , 5- [3- [[3- [1- (4-Fluorophenyl) -1, 3-dihydroiso-benzofuran-1-yl] propyl] methylamino] propyl] -1,4-benzo-dioxane (2 j): LC / MS (m / z) 462 (MH +), Rt = 4.21. purity: 93%. 5- [3- [[3- [1- (3-Trifluoromethylphenyl) -1, 3-dihydroisobenzofuran-1-yl] propyl] methylamino] propyl] -1, -benzodioxane (2k): LC / MS (m / z) ) 512 (MH +), Rt = 4.59, purity: 90%. 1 ~ [3- [[3- (1, 4-Benzodioxan-5-yl) propyl] methyl-amino] propyl] -1- (4-chloro-enyl) -1,3-dihydroisobenzo-furan-5-carboni trilo (21): LC / MS (m / z) 503 (MH +), Rt = 4.59, purity: > 99% 1 - [3 - [4 - (1 H- Indol-4-yl) piperazinyl] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2m): LC / MS (m / z) 481 (MH +), Rt = 5.61, purity: 97%. l- [3- [4- (li-Indol-5-yl) piperazinyl] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2n): LC / MS (m / z) 481 (MH +), Rt = 5.69, purity: 94%. 1- [3- [4- (6-chloro-lJ? -Indol-3-yl) piperidinyl] -propyl] -1- (4-fluorophenyl) -1,3-dihydr oi s oben zof ur an- 5 - ca rbon itri 1 or (20): LC / MS (m / z) 514 (MH +), R t = 6.38, purity: 96%.

E j p a 3 5- [3- [[3- [-5-Fluoro-l- (4-f luoryl) -1, 3-dihydroisobenzofuran-1-yl] propyl] methylamino] propyl] -1, 4 - b in z odi oxa not oxalate (3). A solution of 3 (1, -benzodioxan-5-yl) propionic acid (0 g 3 mmol), thionyl chloride (1 mL, 13.7 mmol) and one drop of N, N-dimethyl thiomide in dichloromethane (30 mL ") were added. It boiled under reflux for 2 hours.

The volatile solvents were evaporated invariably and the remaining oil was dissolved in dichloromethane (30 mL). The remaining solution was added to a solution of [3 - [- 5-fluoro-l- (4-fluorophenyl) -l, 3-dihydr oi s oben zof ur an - 1 - i 1] pr op i 1] me ti Laminate (3.0 g, 10 mmol) and triethylamine (10 mL) in dichloromethane (100 mL). After stirring for 16 hours the volatile solvents were evaporated i n va c uo, and the remaining oil was purified by column chromatography (ethyl acetate / heptane 75:25), obtaining 1.4 g of crude amide, which was used without purification. To a solution of the amide (1.4 2.8 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydride (1.0 g, 2.6 mmol). After bubbling the remaining mixture under reflux for 3 hours, the reaction mixture was cooled to 0 ° C, and carefully treated with water (1 mL) and 4N aqueous sodium hydroxide (1 mL). The remaining mixture was filtered and dried (Na 2 SO 4) the evaporation of the volatile solvents achieved by the title compounds as an oil, which was precipitated as its oxalate in acetone 0.9 g (19%): mp. 131-33 ° C; XH NMR (DMSO-d6) d 1.35-1.45 (m, 1H), 1.45-1.55 (m, 1H), 1.75-1.80 (m, 2H), 2.10-2.25 (m, 2H), 2.50-2.55 (m, 2H), 2.60 (s, 3H), 2.90 (t, 2H), 2. 95 (t, 2H), 4.20-4.25 (m, 4H), 5.10 (m, 2H), 6.65-6.75 (m, 3H), 7.10-7.15 (m, 4H) 7.45-7.60 (m, 3 H); MS m / z 480 (MH +, 100), 225 (34), 109 (51).

Use 4 1- [3- [[2- (lH-Indol-3-yl) ethyl] methylamino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-ca rboni tri 1 or (4a) To a resin suspension Wang acrylic ester (CH2CHC (0) 0 R ', HOR' = Wang resin) (load 1.0 mmol / g) (300 mg, 0.30 mmol) (prepared from Wang resin (Load 1.09 mmoles / g, 200-400 mesh, 1% divinylbenzene) analogous to the procedure described for the preparation of acrylic ester hydroxymethyl polystyrene by Brown et al., J. Am. Chem Soc., 1997, 119, 3288-95) in N, N-dimethylformamide (1.5 mL), was added a solution of 2 - (1 H- in do 1 i 1 - 3 - i 1) eti 1 amine ( 96 mg, 0.60 mmoles) in N, N-dimethyl t-1-methyl (1.5 mL). After stirring the remaining suspension at room temperature for 16 hours, the resin was separated by filtration, subsequently washed with 0.3 M diisopropylethylamine in N, N-d-imethi-1-dimimated (3 X 2.5 mL), methanol (2 X 2.5). mL) and dichloromethane (2 X 2.5 mL).

To a suspension of the excess resin in acetonitrile (1.5 mL) was added a solution of 1- (3-chloropropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenz of ur an-5-ca rboni tri (9) (473 mg, 1.5 mmol) in acetonitrile (1.5 mL) and diisopropylethylamine (280 mL, 1.6 mmol). After heating the remaining mixture at 75 ° C under stirring for 16 hours, the resin was separated by filtration. The resin was then washed with acetonitrile (3 X 2.5 L), methanol (3 X 2.5 mL) dichloromethane (3 X 2.5 mL). The resin was suspended in N, N-dimethyl-1-dimethylamine and diisopropylethylamine (280 mL, 1.6 mmol) and acetic anhydride (140 mL, 1.5 mmol) was added. After stirring the remaining mixture for 16 hours, the resin was separated by filtration and washed with N, N-dimethylammonium (3 X 2.5 mL), methanol (3 X 2.5 mL), and dichloromethane (3 X). 2.5 mL). The intermediate resin was suspended in N, N-dimethoxypropionate (2 mL), a solution of iodomethane (187 mL, 3.0 mmol) in N, N-dimethylformamide was added. After stirring the remaining mixture for 16 hours at room temperature, the resin was separated by filtration and washed with N, N-dimethylammonium (3 X 2.5 mL), methanol (3 X ~ 5 mL). ) and dichloromethane (3 X 2.5 mL). To The remaining resin was added with N, N-d-ime t-1-one (3.0 mL) and Di-i-s or op-1-e-1-amine (165 mL, 0.94 mmol) and the mixture was stirred for 16 hours. The resin was separated by filtration and washed with methanol (2 X 2.0 mL). The decomposition solution and the washing solutions were collected, and the solvent was evaporated in a vacuum. The remaining oil was purified by ion exchange chromatography, using a 6 mL Varian SCX column (1225-6011). The column was preconditioned previously with 10% acetic acid in methanol (3 mL) and the unpurified product was loaded onto the column in a 2: 1 mixture of methanol and 1-methyl 1-2. pyrr ol i dinone (3 mL). After the column was washed with methanol (18 mL) and acetonitrile (3 mL), the product was eluted from the column with 4 N ammonia in methanol (4 mL) and the subsequent evaporation of the in-van solvents achieved 13, 9 mg (10%) of the title compound as an oil: LC / MS (m / z) 454 (MH +), Rt = 6.13, purity: 98%. The following compounds were prepared analogously: 1- (4-Fluorophenyl) -1- [3- [[2- (3-methoxyphenyl) -ethyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile ( 4b): LC / MS (m / z) 445 (MH +), Rt = 8.58, purity: 88%. 1- (4-fluorophenyl) -1- [3- [[2- (3-methoxyphenyl) -ethyl] (prop-2-en-l-yl) amino] propyl] -1,3-dihydroisobenzofuran 5-carbonyl trile (4c): XH NMR (CDC13) d 1.30-1.60 (m, 2H), 2.00-2.2 (m, 2H), 2.40-2.55 (m, 2H), 2.55-2.70 (m, 4H), 3.00-3.15 (broad s, 2H), 3.80 (s, 3H), 5.05-5.20 (m, 4H), 5.75-5.85 (m, 1H), 6.65-6.80 (m, 3H), 7.00 (t, 2H), 7.20 (t, 1H), 7.30 (d, 1H), 7.40 (m, 2H), 7.50 (s, 1H), 7.60 (d, 1H), LC / MS (m / z) 471 (MH +), Rt = 8.85, purity: 91%. - 1- (4-Fluorophenyl) -1- [3- [[2- (2-methoxy-enyl) -ethyl] (prop-2-en-l-yl) -amino] -propyl] -1,3-dihydroiso-benzofuran -5-carbonitrile (4d): H NMR (CDC13) d 1.25-1.40 (m, 1H), 1.40-1.55 (m, 1H), 2.05-2.25 (m, 2H), 2.40-2.50 (m, 2H), 2.50-2.65 (m, 2H), 2.65-2.75 (m, 2H), 3.00-3.15 (m, 2H), 3.80 (s; 3H), 5.05-5.20 (m, 4H), 5.75 -5.90 (m, 1H), 6.75-6.90 (m, 2H), 6.95-7.10 (m, 3H), 7.20 (t, 1H), 7.30 (d, 1H), 7.35-7.45 (m, 2H), 7.45. (s, 1H), 7.60 (d, 1H); LC / MS (m / z) 471 (MH +), R t = 7.82, purity: > 89% l- [3 - [[2- (2,5-Dimethoxyphenyl) ethyl] methyl-amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5-carbonitrile (4e): LC MS (m / z) 475 (MH *), R t = 8.68, purity: 94%. 1- [3- [[2- (2, 5-Dimethoxyphenyl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1, 3- dihydr oi so-benz ofuran-5-carbonyl tri lo (4f): LC / MS (m / z) 500 (MH +), Rt = 8.95, purity: 90%. 1- (4-Fluorophenyl) -1- [3- [[2-phenoxyethyl] methyl-amino] propyl] -1,3 -dihi dr ois oben zof ur an-5-ca rboni tri 1 or (4g): LC MS (m / z) 431 (MH +), R t = 8.58, purity: 95%. 1- [3- [[2 - (lH-Indolyl-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroiso- ben zof ur an-5-ca rboni tri 1 or (4h): LCMS (m / z) 480 (MH +), R t = 8.87, purity: 93%. 1- (4-Fluorophenyl) -1- [3- [[2-phenoxyethyl] (prop-2-en-l-yl) amino] propyl] -1, 3 -di hi dr ois ob in zofuran-5-ca rbon itri 1 or (4i): LC / MS (m / z) 457 (MH +), Rt = 6.40. purity: > 99% l- (4-Fluorophenyl) -l- [3- [[3- (2-methoxyphenyl) -propyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4j): LC / MS (m / z) ) 459 (MH +), Rt = 6.43, purity: > 99% 1- (4-Fluorophenyl) -1- [3- [[3- (2-methoxyphenyl) -propyl] (pr op-2-en-1-i 1) ami no] pr op i 1] - 1, 3 -di hi hi oiso -benzof ur an - 5 - ca rb oni trilo (4k): LC / MS (m / z) 485 (MH +), Rt = 6.77, purity: > 99% 1- (4-Fluorophenyl) -1- [3- [[3- (3-methoxy-enyl) -propyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroiso- ben z or f uran-5-ca rboni tryl (41): LC / MS (m / z) 485 (MH +), R t = 6.63, purity: > 99% l- (4-Fluorophenyl) -l- [3- [[3- (2-methoxyphenoxy) -propyl] methylamino] propyl] - 1, 3 -di hi dr ois oben zofur an - 5 - ca rb on itri 1 o (4m): LC / MS (m / z) 475 (MH +), Rt = 6.20. purity: >; 99% 1- (4-Fluorophenyl) -1 - [3 - [[3- (2-ethoxyphenoxy) propyl] (prop-2-en-l-yl) amino] propyl] -1, 3 - di hi dr ois oben zofuran - 5 - carb oni tri 1 or (4n): LC / MS (m / z) 501 (MH +), Rt = 6.50. purity: > 99% 1- (4-Fluorophenyl) -1- [3- [[3- (3-methoxyphenoxy) -propyl] methylamino] propyl] -1, 3 -di hi dr oi s oben zof ur an - 5 - ca rboni tri 1 or (40): LC / MS (m / z) 475 (MH +), Rt = 6.35, purity: > 99% l- (4-Fluorophenyl) -l- [3- [[3- (3-methoxyphenoxy) -propyl] (prop-2-en-l-yl) amino] propyl] -1, 3 -di hi dr o- is oben zof ur an- 5-ca rbon itri 1 or (4 p): LC / MS (m / z) 501 (MH +), R t = 6.65, purity: > 99% 1- [3- [(2-Benzyloxyethyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisabenzofuran-5-carbonitrile (4q): LC / MS (m / z) 445 (MH +), Rt = 618, purity: > 98%. 1- [3- [(2-Benzyloxyethyl) (prop-2-en-l-yl) -amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo- furan-5-carbonyl trile (4r): LC / MS (m / z) 471 (MH +), Rt = 6.55, purity: > 97%. 1 ~ [- [[3 - (1 H- Indol-3-yl) propyl] methylamino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4s): LC / MS (m / z) 468 (MH +), Rt = 6.28, purity: 80%. 1 - [3- [[3- (l-l-Indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl-1,3-dihydroiso) -benz of uran-5-ca rboni trilo (4t): LC / MS (m / z) 494 (MH +), R t = 6.60, purity: 82% 1- [3- [[3- (l-i-Indol- 3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo furan-5-ca rboni tri 1 or (4u) LC / MS (m / z) 492 (MH +), R t = 6.59, purity: 73%.

E j us 5 5 -h i dr oxime t i 1 - 1, 4 -b in z or di or x a n o (5). To a suspension of aluminum hydride (7.0 g, 0.18 mol) in dry diethyl ether (100 mL), was added a solution of ethyl 1,4-benz odi oxan-5-ca rbox i 1 to t o (35 g, 0.17 mol) in diethyl ether (100 mL). After bubbling under reflux for 2 hours, the reaction mixture was cooled to 0 ° C and carefully treated with water (35 mL) and 4 N aqueous sodium hydroxide (35 mL). The leftover mixture was filtered and dried (Na 2 SO 0). Evaporation of the solvents achieved 25 g (88%) of the crystalline title compound: mp. 51-53 ° C; XH NMR (CDC13) d 2.50 (s, 1H), 4.20-4.3 (m, 4H), 4.60 (s, 2H), 6.75-6.90 (m, 3H).

Example 6 2 - (1, 4 -ben zodioxan-5-i 1) a cé t i co (6) acid. To a solution of 5-hydroxy-di-1-l, 4-benzodioxane (8.0 g, 48 mmol) in dichloromethane (200 mL) were added N-dimethyl-1-fluoride drops and sodium chloride. thionyl (5.0 mL, 68 mmol) at room temperature. After the remaining solution was bubbled under reflux for 1 hour, and subsequently cooled to room temperature water (100 mL) was added. The phases were separated and the organic phase was dried (MgSO.sub.4) and the solvents were evaporated. A solution of the remaining oil (8.5 g, 46 mmol) was added to a mixture of sodium cyanide (5.0 g, 102 mmol) and dimethyl ether (100 mL) at room temperature. After stirring for 16 hours at room temperature, ice was added and the remaining suspension was extracted with diethyl ether (2 X 250 mL). The collected organic phases were washed with saturated calcium chloride, dried (Na2SO) and the solvents were evaporated in a vacuum. A mixture of the remaining oil (6.0 g, 34 mmol), ethanol (200 mL), sodium hydroxide (6.0 g) and water (6 L) was bubbled under reflux for 16 hours. After evaporation of the solvents i n va c u o, water (200 mL) was added and the remaining suspension was extracted with diethyl ether (2 X 200 mL). The collected organic phases were washed with brine, dried (Na2SO4) and the solvents were evaporated in vacuo, yielding 4.0 g (43%) of the title compound as an oil: XH NMR (CDC13) d 3.65 (s, 2H), 4.15-4.30 (m, 4H), 6.70-6.85 (m, 3H).

Example 7 5 - (2-b r o oe t i 1) - 1, 4 -ben z odi oxano (7a). To a solution of 2-b in z odi oxa n-5-i 1) to acetic acid (6) (4.0 g, 21 mmol) in tetrahydrofuran (200 m) was added lithium aluminum hydride (1.0 g, 26 mmol) ). After bubbling under reflux for 2 hours, the reaction mixture was cooled to 0 ° C, and carefully treated with water (1 mL) and 4N aqueous sodium hydroxide (1 mL). The remaining mixture is filtered and dried (Na 2 SO 4). The evaporation of the solvents was achieved with unpurified intermediate alcohol (3.9 g, 21 mmol) as an oil, which it was used without another purification. To a solution of the intermediate alcohol and tetrabromomethane (8.8 g, 27 mmol) in acetonitrile (120 mL) was added triphenylphosphine (6.3 g, 24.9 mmol) in small portions at 0 ° C. After the reaction for a further 15 minutes at 0 - the solvents were evaporated i n va c uo, and the remaining oil was purified by column chromatography (ethyl acetate / heptane 66:34), achieves 5.5 g (99%) of the title compound as an oil. 1 H NMR (CDC13) d 3.15 (t, 2 H), 3.55 (t, 2H), 4.20-4.35 (m, 4H), 6.65-6.85 (m, 3H). The following compounds were prepared analogously: 5- (3-B r omop r op i 1) -1,4-benz odi oxa no (7b): (oil) x ñ NMR (CDCl 3) d 2.15 (quin, 2H ), 2.75 (t, 2H), 3.40 (t, 2H), 4.20-4.30 (m, 4H), 6.65-6.75 (m, 3H). 5 - (4-Br omobu ti 1) - 1.4 -ben z odi oxa no (7c): (oil) 1 H NMR (CDC13) 6 1.70-1.80 (qui, 2H), 1.85-1.90 (qui, 2H), 2.60 (t, 2H), 3.40 (t, 2H), 4.25 (m, 4H), 6.65-6.75 (m, 3H). 1 - (2 -Br omoe t oxy) -2-methyl t-benzene (7d): (oil) -i NMR (CDCl 3) d 3.65 (t, 2H), 3.85 (s, 3H), 4.30 (t, 2H), 6.80-7.05 (m, 4H). 1 - . 1 - (2 -B r omoe t oxy) - 3 -me t ox ibenzene (7e): (oil) H NMR (CDC13) d 3.60 (t, 2H), 3.80 (s, 3H), 4.25 (t, 2H), 6.45-6.55 (m, 3H), 7.15 (t, 1H).

Example 8 4- (1,4-Benzodioxan-5-yl) butanoic acid (8a) 5 - (4-b r omoe t i 1) - 1, 4 - b e n z o di oxa n o (7c) pure (18.0 g, 74 mmol) was added to a mixture of malonate (12 g, 75 mmol), potassium tert-butoxide (8.4 g, 75 mmol), toluene (250 mL) and dimethyl sulfoxide (50 mL) at room temperature . The remaining mixture was heated at 50 ° C for 3 hours, cooled to room temperature and water was added. After the suspension was acidified with concentrated hydrochloric acid, the phases were separated. The organic phase was dried (Na 2 SO 4) and the solvents were evaporated. The remaining oil was dissolved in ethanol (200 mL) and 9N aqueous sodium hydroxide. After bubbling the remaining mixture under reflux for 15 minutes, the solution was stirred at room temperature for 1 hour. The solvents evaporated and the remaining oil was diluted in water (200 mL) and extracted with diethyl ether (2 X 100 mL). The aqueous phase was acidified with 4N hydrochloric acid and extracted with ethyl acetate (2M).

X 200 mL). The drying of the collected organic phases and the evaporation of the solvents were carried out as the intermediate dicarboxylic acid was supplied as an oil (5.0 g,). The crude oil was diluted in pyridine (10 mL) and the remaining solution was heated at 115 ° C for 1 hour. After cooling to room temperature, water (50 mL) was added and the aqueous phase was acidified with 4N hydrochloric acid. The remaining suspension was extracted with diethyl ether (2 X 50 mL) and the collected organic phases were dried (Na2SO4). The evaporation of in va c u o solvents achieved 3.8 g (23%) of the compound as an oil. The following compound was prepared analogously: 3- (1,4-Benzodioxan-5-yl) propionic acid (8b): (oil) XH NMR (CDC13) d 2.65 (t, 2H), 2.95 (t, 2H) , 4.20-4.30 (m, 4H), 6.65-6.80 (m, 3H).

EXAMPLE 9 1- (3-Chloropropyl) -1- (4-fluorophenyl) -1,3-dihi dr oi s obenz or f ur an- 5-ca rbon i t r i l-o (9). To a mixture of 1 - [3 - (me t i 1 ami n o) p r op i 1] - 1 - (4 - f 1 u o r o f e n i 1) 1,3 dih i dr oi s oben z o f ur an - 5 - ca rbon i t r i 1 o (43 g, 138 mmol), potassium carbonate (30 g, 217 mmol) and Ethanol (400 mL) was added ethyl bromoacetate (20 mL, 1-0 mmol) at room temperature, and the remaining mixture was boiled under reflux for 90 minutes. After cooling to room temperature, water (800 mL) and ethyl acetate (500 mL) were added and the phases were separated. The organic phase was washed with brine, dried (Na 2 SO 4) and the solvents were evaporated in vacuo. The remaining oil (36 g, 101 mmol) was slowly added to a mixture of ethyl chloroformate (50 mL, 523 mmol), potassium carbonate (36 g, 260) and toluene (300 mL) at 90 ° C. After bubbling the remaining mixture under reflux for 1 hour and cooling to room temperature, the solvents were evaporated i n va c u o. The remaining oil was purified by column chromatography (ethyl acetate-heptane 1: 3), giving 15 g, (34%) of the title compound as an oil: XH NMR (CDC13) d 1.60-1.90 (m, 2H), 2.20-2.45 (m, 2H), 3.45-3.55 (m, 2H), 5.20 (m, 2H), 6.95-7.10 (t, 2H), 7.40-7.55 (m, 4H), 7.60 (d, 1 HOUR) .

Example 10 [2 - (2 -Me t ox i f enoxi) e t i 1] me t i lamí na (10a). A solution of 1 - (2-br omoe t ox i 2 -me t oxibenzene (7d) (7.7 g, 33 mmol) was heated in a 33% solution of methylamine of ethanol at 80 ° C in a sealed tube for 16 hours. After cooling to room temperature, the solvents were evaporated and a 2N aqueous solution of sodium hydroxide was added to the remaining oil, the remaining suspension was extracted with ethyl acetate (2 X 250 mL). The collected organic phases were dried (Na2SO4) and the solvents were evaporated in vacuo, giving 5.9 g, (98%) of the title compound as an oil: 1 H NMR (CDC13) d 1.85 (broad s, 1H), 2.50 ( s, 3H), 3.00 (t, 2H), 3.85 (s, 3H), 4.10 (t, 2H), 6.85-6.95 (m, 4H). The following compound was prepared in a manner analogously: [2 - (3-Me t-oxy-enoxy) eti 1] me-thi-amine (10b): (oil) 1 H NMR (CDC13) d (broad s, 1H), 2.50 (s, 3H), 2.95 (t, 2H), 3.80 (s, 3H), 4.05 (t, 2H), 6.45-6.55 (m, 3H), 7.15 (t, 1H).

Example 11 2- (4-Chlorobutyl) -dioxolan-4-ylmethoxymethyl polystyrene (lia). In a round-bottomed container was charged with 2, 2-dimethyl-1-di-oxo-1-an-4-ymethyl-im-t-yl-polystyrene (90 g, 72 mmol, commercially available as (±) - 1 - (2, 3 - is op r op i 1 i deno) glycerol polystyrene, from Ca lbi ochem-No vabi ochem, cat. do not. 01-64-0291). Toluene (900 mL) was added, followed by p-toluenesulfonic acid monohydrate (5.0 g, 26 mmol), sodium sulfate (25 g), and 5-c 1 or open t ana 1 readily available (25.5 g, 211 mmol) ), and the mixture was heated to reflux for 12 hours. The reflux condenser was replaced by a Dean-Stark apparatus, and the mixture was heated to reflux for an additional 3 hours. After cooling the reaction mixture to 60 ° C, the resin was filtered and washed with toluene (200 L), tetrahydrate of no / pyridine (1: 1, 200 mL), tetr ahi dr of ur ano / a gua / pi r idine (10: 10: 1, 200 mL), methanol (200 L), water (200 mL), tetrahydrofuran (200 mL), dichloromethane (200 mL), methanol (3 X 200 mL), and dichloromethane ( 3 X 200 mL). The resin was dried (55 ° C, 12H) to yield the title compound lia (97g). The following compounds were prepared analogously: 2- (3-Chloropropyl) -dioxolan-4-ylmethoxymethyl polystyrene (11b) 2- (5-Chloro-entyl) -dioxolan-4-ylmethoxymethyl polystyrene (11c) Example 12 1 - [3 - [[3 - (1 H- Indol-3-yl) propyl] methylamino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4s). It was suspended in dry 2- (4-C 1 or obu t i 1) - di oxo 1 an - 4 - i lme t oxime t i 1 polystyrene (lia) (8.0 g, 6.1 mmoles) in N, N-dime t i 1 f ormami ia (90 mL). Sodium iodide (3.38 g, 22.5 mmol) was added, followed by diiso ropylethylamine (6.30 mL, 36 mmoles) and 1 - [3 - (e t i lamino) pr opi 1] - 1 - (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (5.56 g, 18 mmol). The reaction mixture was heated to 80 ° C under stirring for 12 hours. After cooling to room temperature, the resin was filtered and washed with N, N-dimethylformamide (3 X 65 mL), methanol (3 X 60 mL), tetrahydrofuran (3 X 60 mL) and subsequently with methanol and tetrahydrofuran ( each approximately 40 mL, 5 cycles). Finally, the resin was washed with tetrahydrofuran (4 X 40 mL) and dried (55 ° C, 12 h, 9.5 g). An aliquot of this material (147 mg, 0.112 mmol) and f eni lhi dr a z i na hydrochloride (43 mg, 0.297 mmol) were mixed in a reactor tube. A 0.5 M solution of anhydrous zinc chloride in acetic acid (1.5 mL) was added, and the reaction was sealed in a tube. The reaction mixture was stirred for 12 hours at 75 ° C. After cooling to room temperature, the reaction mixture was filtered and the remaining resin was washed with dimethyl sulfoxide (1.5 mL). A solution of saturated aqueous sodium bicarbonate (1.5 mL) was added to the combined filters. The solution was loaded on a reverse solid phase extraction column (C-18), 1 g, Variety Mega Bond Elut®, Chrompack cat. do not. 220508), previously conditioned with methanol (3 mL) and water (3 mL). The column was washed with water (4 mL) and the product was eluted with methanol (4.5 mL). The remaining solution was loaded onto an exchangeable ion column (SCX, 1 g, Varigan Mega Bond Elut®, Chrompack cat 220776), preconditioned with 10% acetic acid solution in methanol (3 mL), and the column was washed with methanol (4 mL) and acetonitrile (4 mL), followed by elution with 4N ammonia solution in methanol (4.5 mL), evaporation of the volatile solvents gave the title compound (4s) as a colorless oil (22 mg, 42 mg). %). LC / MS (m / z) 468 (MH +), R t = 4.30. 83% purity. The following compounds were prepared analogously: 1- [3- [[2- (5-Methyl-2i-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-f-uran-5-carbonitrile (12a): LC / MS (m / z) 468 (MH +), Rt = 4.22, purity: 96%. 1- [3- [[2- (7-Fluoro-H-indol-3-yl) ethyl] -methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12b H NMR CDC13 d 1.2-1.4 (m, 1H 1.4-1.55 m, 1H), 2.0-2.25 (m, 2H), 2.25 (s, 3H), 2.39 (t, 2H), 2.60 (t, 2H), 2.86 (t , 2H), 5.05-5.21 (m, 2H), 6.93-7.07 (m, 4H), 7.17-7.3 (m, 2H), 7.3-7.4 (m, 3H) 7.4-7.5 (m, 1H), 7.5-7.6 (m, 1H); LC / MS (m / z) 472 (MH +), Rt = 4.12, purity 86%. 5-Fluoro-l- [3- [[3- (5-methyl-liT-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorsphenyl) -1,3-dihydroisobenzofurane (12c) LC / MS (m / z) 475 (MH +), Rt = 4.57, purity: 92%. 5-Fluoro-l- [3- [[3- (7-fluoro-lly-indol-3-yl) -propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofurane (12d) ): LC / MS (m / z) 479 (MH +), Rt = 4.47, purity: 94%. 1- [3- [[3- (5-Methyl -indol-3-yl) propyl] -methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydro-i s obenz of uran-5-ca rboni trile (12e): LC / MS (m / z) 482 (MH *), R t = 4.54, purity: 80%. 1- [3- [Ethyl [3- (lff-indol-3-yl) propyl] amino] -propyl] -1- (4-f luorofenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12f): LCMS (m / z) 482 (MH +), Rt = 4.31, purity: 94%. l- [3- [Ethyl [2- (5-methyl-2i? -indol-3-yl) ethyl] -amino] propyl] -1- (4-fluorophenyl) -1,3-dihydro-1-sobenzofuran 5-carbonyl trile (12 g): LC / MS (m / z) 482 (MH +), R t = 4.38. purity: 89%. 1- [3- [[3- (7-Fluoro-2H-indol-3-yl) propyl] -methylamino] propyl] -1- (4-fluorophenyl) -1, 3 -di hi dr oi s oben zof ur an-5-carboni tri 1 or (12h): LC / MS (m / z) 486 (MH +), Rt = 4.16. purity: 79%. 1 - [3- [[3- (5-Fluoro-2H-indol-3-yl) propyl] -methylamino] propyl] -1- (4-fluoro f ni 1) - 1,3-di hi dr oís oben zof ur an - 5 - ca rboni tri 1 or (12i): XH NMR (CDC13) d 1.23-1.39 (m, 1H), 1.39-1.54 (m, 1H), 1.80 (tt, 2H), 2.06-2.24 ( m, 5H), 2.30 (t, 2H), 2.34 (t, 2H) 2.68 (t, 2H), 5.13 (d, 1H), 5.17 (d, 1H), 6.93 (dt, 2H), 6.99 (t, 2H), 7.21 (dd, 1H), 7.23-7.29 (m, 1H), 7.33 (d, 1H), 7.40 (dd, 2H) 4.47 (s, 1H), 7.55 (d, 1H), 8.01 (s, 1 HOUR ); LC / MS (m / z) 486 (M H), R t = 4.12, purity: 98%. l- [3- [Ethyl [2- (5-fluoro-2--indol-3-yl) ethyl] -amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5 -carbonitrile (12j): XH NMR (CDCl3), d 1.02 (t, 3H), 1.25-1.38 (m, 1H), 1.42-1.54 (m, 1H), 2.10 (ddd, 1H), 2.18 (ddd, 1H), 2.49 (t, 2H), 2.56 (q, 2H) ), 2.61-2.70 (m, 2H), 2.74-2.82 (, 2H), 5.13 (d, 1H), 5.18 (d, 1H), 6.94 (dt, 2H), 6.99 (t, 2H), 7.19 (dd) , 1H), 7.23-7.30 (m, 2H), 7.38 (dd, 2H), 7.47 (s, 1H), 7.54 (d, 1H), 8.01 (s, 1 H); LCMS (m / z) 486 (MH +), Rt = 4.24, purity: 95%. 1- [3- [Ethyl [2- (7-fluoro-l-indol-3-yl) ethyl] -amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran - 5 - ca rboni t ril (12k) H NMR (CDC13) 1. 02 (t, 3H), 1.22-1.37 (m, 1H), 1.42-1.53 (m, 1H), 2.0-2.2 (m, 2H), 2.36-2.6 (m, 4H), 2.67 (t, 2H), 2.81 (t, 2H), 5.12 (dd, 1H), 5.16 (d, 1H), 6.86-7.06, 4H 7.2-7.4 (m, 5H 7. 6 d 1H 7.54 d, 1 HOUR); LCMS (m / z) 486 (MH +), R t = 4.26, purity: 91%. 1- t 3- [[2- (5-Chloro-2H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroiso-benzofuran-5-carbonyl tryl (121): LC / MS (m / z) 488 (MH +), Rt = 4.30. Purity: 85%. 1- [3- [[3- (5-Chloro-2i-indol-3-yl) propyl] -methylamino] propyl] -5-fluoro-l- (4-fluorophenyl) -1,3-dihydroisobenzofurane (12m ): LC / MS (m / z) 495 (MH +), Rt = 4.64, purity: 94%. l- [3 - [[4- (5-Methyl-2JI-indol-3-yl) butyl] -methylamino] propyl] -1- (4-fluorofenyl) -1,3-dihydro- i s oben z o f ur a - 5 - ca rboni t r i lo (12 n): LC / MS (m / z) 496 (MH +), Rt = 4.50. purity: 78%. 1- [3- [Ethyl [3- (5-methyl-2 - "- indol-3-yl) -propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydro-1 s or in z of uran - 5 - carboni tri 1 or (12o): LC / MS (m / z) 496 (MH +), Rt = 4.50. purity: 92%. 1- [3- [Ethyl [3- (7-fluoro-2i-indol-3-yl) -propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydro-i s obenz of ur an - 5 - ca rboni tri lo (12p): LC / MS (m / z) 500 (MH *), Rt = 4.39, purity: 91%. l- [3- [Ethyl [3- (5-fluoro-2-indol-3-yl) -propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydro-isobenzofuran-5 - c arboni tri 1 or (12q): 1H NMR (CDC13) d 0.95 (t, 3H), 1.21-1.36 (m, 1H), 1.36-1.50 (m, 1H), 1.77 (tt, 2H), 2.10 ( ddd, 1H), 2.18 (ddd, 1H), 2.34-2.50 (m, 6H), 2.65 (t, 2H), 5.12 (d, 1H), 5.15 (d, 1H), 6.90-7.04 (m, 4H) 7.20 (dd, 1H), 7.25 (dd, 1H), 7.30 (d, 1H), 7.3 & (m, 2H), 7.45 (s, 1H), 7.52 (d, 1H), 8.12 (s, 1 H); LCMS (m / z) 500 (MH *), Rt = 4.35, purity: 94%. l- [3 - [[3- (5-Chloro-2J? -indol-3-yl) propyl] -methylamino] propyl] -1- (4-fluorophenyl) -1, 3-dihydro-i s obenz or fur an- 5 - ca rboni tri 1 or (12r): LC / MS (m / z) 502 (MH *), Rt = 4.55, purity: 91%. 1- [3- [[2- (7-Chloro-1-yl-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5-carbonitrile ( 12s): LC / MS (m / z) 502 (MH *), Rt = 4.41, purity: 80%. 1- [3- [[2- (5-Chloro-2i? -indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-f-uran-5-carbonitrile (12t): LC / MS (m / z) 502 (MH *), Rt = 4. 4, purity: 95% l- [3 - [[2- (5.7-Difluoro-2H-indol-3-yl ) ethyl] -ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroiss-benzo furan-5-ca rboni trilo (12u): LC / MS (m / z) 504 (MH *) , Rt = 4.35, purity: 92% 1- [3- [[4- (5-Fluoro-lH-indol-3-yl) butyl] -ethylamino] propyl] -1- (4-fluorophenyl) -1 , 3-dihydro-i s obenzo f ur an- 5-carboni tri lo (12v): LC / MS (m / z) 514 (MH *), Rt = 4.50, purity: 91% l- [3- [ [4- (5-Chloro-2-indol-3-yl) butyl] -methylamino] propyl] -1- (4-fluorofenyl) -1,3-dihydroisobenzofur an-5-ca rboni tri lo (12w): LC / MS (m / z) 5.16 (MH *), Rt = 4.59, purity: 90% 1- [3- [[3- (5-Chloro-22-indol-3-yl) ) propyl] -ethylamino] propyl] -1- (4-fluorophenyl) -1, 3-dihydro-i s obenz of uran-5-carbonyl trile (12x): LC / MS (m / z) 5.16 (MH *) , Rt = 4.56, purity: 97%. 1- [3- [[3- (5, 7-Difluoro-2ff-indol-3-yl) -propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1, 3 -dihi dr oi s oben zof ur an- 5-ca rboni tri 1 or (12y): LC / MS (m / z) 518 (MH *), Rt = 4.47, purity: 90%. 1- [3- [[2- (5-Bromo-2i? -indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-f-uran-5-carbonitrile (12z): LC / MS (m / z) 532 (MH *), Rt = 4.46, purity: 87%. l- [3- [[3- (5-Bromo-2-indol-3-yl) propyl] -methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydro-i s oben zof ur an- 5-ca rboni tri 1 or (12aa): LC / MS (m / z) 546 (MH *), R t = 4.59, purity: 88%. l- [3- [[2- (5-Bromo-2H-indol-3-yl) ethyl] ethyl-amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5- carbonitrile (12ab): LC / MS (m / z) 546 (MH *), Rt = 4.50. Purity: 90%. l- [3- [[4- (5-Bromo-2-_-indol-3-yl) butyl] -methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydro-isomers of ur an - 5 - ca rbonid tri 1 or (12 ac): LC / MS (m / z) 560 (MH *), R t = 4.61, purity: 90%. 1- [3- [[3- (5-Bromo-2i-indol-3-yl) propyl] -ethylamino] ropil] -1- (4-fluorophenyl) -1,3-dihydroiso-benzofuran-5- carbonyl t (12ad): LC / MS (m / z) 560 (MH *), Rt = 4.62, purity: 92%. 1- [3- [Ethyl [2- (5-iodo-2H-indol-3-yl) ethyl] -amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5 -carbonitrile (12ae): LC / MS (m / z) 594 (MH *), Rt = 4.60, purity: 82%. l- [3- [Ethyl [3- (5-iodo-li? -indol-3-yl) propyl] -amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5 -carbonitrile (12af): LC / MS (m / z) 608 (MH *), Rt = 4.72, purity: 71%. 1- [2- [[4- (5-Chloro-1-indol-3-yl) butyl] -methylamino] ethyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofur an- 5-ca rboni tri 1 or (12ag): LC / MS (m / z) 502 (MH *), Rt = 4.50. Purity: 90%. 1- [2- [[4- (5-Bromo-2-yl-indol-3-yl) butyl] -methylamino] ethyl] -1- (4-fluorophenyl) -1,3-dihydroiso-benzofuran-5- carbonyl trile (12ah): LC / MS (m / z) 546 (MH *), Rt = 4.55, purity: 83%. 1- [4- [[2- (5,7-Difluoro-2 - "- i ndol-3-yl) ethyl] -methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzof Uran-5-ca rbonthyl (12ai): LC / MS (m / z) 504 (MH *), Rt = 4.36, purity: 87% 1- [4- [[2- (7-Chloro-li? -indol-3-yl) ethyl] methylamino] butyl] -1- (4-phlorophenyl) -1,3-dihydroisobenzo-furan-5-carbonitrile (12aj): LC / MS (m / z) 502 (MH * ), Rt = 4.42, purity: 70%. 1- [4- [[2- (5-Chloro-lJ] -indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5- carbonitrile (12ak): LC / MS (m / z) 502 (MH *), Rt = 4.45, purity: 91%. 1- [4- [[2- (5-Bromo-2i-indol-3-yl) ethyl] methyl-amino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5 -carbonitrile (12al): LC / MS (m / z) 546 (MH *), Rt = 4.48, purity: 90%. 1- [4- [[2- (5-Methyl-lJI-indol-3-yl) ethyl] methyl-amino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5- carbonyl trile (12am): LC / MS (m / z) 482 (MH *), Rt = 4.37, purity: 87%. 1- [4- [[2- (5-Iodo-27-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5-carbonitrile (12an ): LC / MS (m / z) 594 (MH *), Rt = 4.57, purity: 83%. 1- [4- [[2- (5- (2-methyl-2-propyl) -2iT-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3 - dihi dr oi s oben zof ur an- 5-carboni tri 1 or (12ao): LC / MS (m / z) 524 (MH *), Rt = 4.85. purity: 91%. 1- [4- [[2- (5- (2-Propyl) -Iff-indol-3-yl) ethyl] -methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydro-1 s obenz of uran-5-carboni trilo (12ap): LC / MS (m / z) 510 (MH *), Rt = 4.72, purity: 92%.

Example 13 1- [3- [[2- (5-Methyl-2ι-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-ca rboni trile (13a) 2 - (3 -C 1 orof eni 1) -1,3-di oxo 1 an-4-i Ime t oxime ti 1 polystyrene (2.0 g, 1.6 mmol) in N, -dime ti 1 dry formamide (15 mL). Sodium iodide (0.67 g, 4.5 mmol is added), followed by diisopropylethylamine (1.70 mL, 9.6 mmol) and allylamine (0.28 g, 4.8 mmol). The reaction mixture was heated to 80 ° C under stirring for 12 hours. After cooling to room temperature, the resin was filtered and washed with N, N-dimethylammonium (3 X 15 mL), methanol (3 X 15 mL) and tetrahydrofuran (3 X 15 mL) therein. Subsequently with methanol and tetrahydrofuran (each 10 mL, 5 cycles). Finally, the resin was washed with tetrahydrofuran (4 X 10 mL) and dried in vacuo (55 ° C, 12 h), then the resin was suspended in dry N, N-dimethylammonium (20 mL). Sodium iodide (0.60 g, 4.0 mmol) was added followed by diisopropylethylamine (0.48 mL, 2.7 mmol) and 1 - (3-cl or op r op i 1) - 1 - (4 - f 1 or of in i 1) -1, 3 - di hi dr oi oben zof ur an - 5 -ca rbon itri 1 o (9) (0.79 g, 2.5 mmoles) The reaction mixture was stirred for 12 hours at 80 ° C. After cooling at temperature At room temperature, the resin was filtered and washed with N, N-dimethylformamide (3 X 15 mL), methanol (3 X 15 mL), tetrahydrofuran (3 X 15 mL) and then subsequently with methanol and tetrahydrofura or (each ca. 15 mL, 5 cycles). Finally, the resin was washed with tetrahydrofuum (4 X 15 L) and dried (c 55 ° C, 12 h, 2.1 g). An aliquot of this material (120 mg, ca. 0.08 mmol) and hydrochloride 4-methyl tetrahydrofuran (ca. 40 mg, 0.20 mmol) were mixed in a reactor tube. A 0.5 M solution of anhydrous zinc chloride in acetic acid (1.5 mL) was added and the reaction tube was sealed. The reaction mixture was stirred for 12 hours at 75 ° C. After cooling to room temperature, the reaction mixture was filtered and the remaining resin was washed with dimethyl sulfoxide (1.5 mL). To the combined filters was added saturated aqueous sodium bicarbonate solution (1.5 mL). The solution was loaded onto a reversed phase column (C-18, 1 g, Varigan Mega Bond Elut®, Chrompack cat.No. 220508), preconditioned with methanol (3 mL) and water (3 mL). The column was washed with water (4 mL) and the product was eluted with methanol (4.5 mL). After the evaporation of the volatile solvents, the product unpurified was purified by preparative by reverse phase HPLC chromatography. The remaining solution was loaded on a column of ion exchange ion (SCX, 1 g, Varigan Mega Bond Elut®, Chrompack cat No. 220776), previously conditioned with 10% solution of acetic acid in methanol (3 mL), and the column was washed with methanol (4 mL) and acetonitrile (4 mL), followed by elution with 4N solution of ammonia in methanol (4.5 mL). Evaporation of the volatile solvents gave the title compound (13a) as a colorless oil (2 mg, 4 μmol, 5%). LC / MS (m / z) 494 (MH *), Rt = 4.44, purity: 93%. The following compounds were prepared analogously: 1- [3- [[2- (5-Fluoro-2i-indol-3-yl) ethyl] - (prop-2-en-1-yl) amino] propyl] - 1- (4-fluorophenyl) -1, 3 -dihi dr ois oben zof uran- 5-ca rboni tri 1 or - (13b): LC / MS (m / z) (MH *), Rt = 4.31, purity: 96%. l- [3 - [[2- (7-Fluoro-lff-indol-3-yl) ethyl] - (prop-2-en-l-yl) amino] propyl] -1- (4-fluorophenyl) -1 , 3 -dih idr oi s oben zof ur an - 5 - ca rbon itri 1 o (13c): LC / MS (m / z) 498 (MH *) Rt = 4.34, purity: 86%. l- [3 - [[3- (5-Fluoro-2H-indol-3-yl) propyl] - (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) - 1, 3- dihi dr oi s oben z or f ur an- 5 - carboni t r i 1 (13d): LC / MS (m / z) 512 (MH *), Rt = 4.48, purity: 96%. 1- [3- [[3- (7-Fluoro-2ii-indol-3-yl) propyl] - (prop-2-en-l-yl) amino] propyl] -1- (4-fluorofenyl) - 1, 3 -di hi dr oi s oben zof ur an- 5-ca rboni tri 1 o (13e): LC / MS (m / z) 512 (MH *), R t = 4.49, purity: 78%. 1- [3- [[2- (5-Chloro-22-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3 - dihi droi s oben zof uran- 5 - ca rboni trilo (13f): LC / MS (m / z) 514 (MH *), Rt = 4.52. Purity: 86%. 1- [3- [[2- (5,7-Difluoro-2-yl-indol-3-yl) ethyl] -propylamino] propyl] -1- (4-fluorophenyl) -1, 3-dihydro-i s obenz of uran - 5 -ca rboni tril or (13g): LC / MS (m / z) 518 (MH *), Rt = 4.47, purity: 89%. l- [3- [[2- (5- (2-Propyl) -lH-indol-3-yl] ethyl] - (2-propyl) amino] propyl] -1- (4-fluorophenyl) -l, 3 -dihi dr ois oben zof ur an - 5 -carboni tri 1 or (13h): LC / MS (m / z) 524 (MH *), Rt = 4.78, purity: 96% .l-t3 - [[3 - (4-Fluoro-7-ethyl-IH-indol-3-yl) -propyl] (pr op-2-en-1-i 1) amino] pr op i 1] - 1 - (4 - f luo ro phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (13i): LC / MS (m / z) 526 (MH *), Rt = 4.65, purity: 83% 1- [3- [[2- ( 4-Chloro-7-methyl-2'-indol-3-yl) -ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluoro- phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (13j): LC / MS (m / z) 528 (MH *), Rt = 4.67. purity: 79%. 1- [3- [[3-. { 5-Chloro-2i? -indol-3-yl) propyl] - (prop-2-en-l-yl) amino] propyl] -1- (4-fluorophenyl) -1, 3 -dihi dr oi s oben zo furan-5-carboni tri 1 or (13k): LC / MS (m / z) 528 (MH *), Rt = 4.63, purity: 78%. l- [3 - [[2- (5-Pyrrolo [3,2-h] -lif-quinolin-3-yl) ethyl] (prop-2-en-l-yl) amino] propyl] -1- ( 4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (131): LC / MS (m / z) 531 (MH *), Rt = 3.43, purity: 91%. 1- [3- t [3- (7-Fluoro-27-indol-3-yl) propyl] (2-furylmethyl) amino] propyl] -1- (4-fluorophenyl) -1, 3 -dihi dr oi s oben zof ur an- 5 - carbon itri 1 or (13m): LC / MS (m / z) 552 (MH *), Rt = 4.58, purity: 82%. l- [3 - [[4- (7-Carboxy-2i-indol-3-yl) butyl] - (prop-2-en-l-yl) amino] propyl] -1- (4-fluorophenyl) -1 , 3 -dihydr oi s oben zof ur an - 5 - carboni tri lo (13n): LC / MS (m / z) 552 (MH *), Rt = 4.17, purity: 69%. 1- [3- [[2- [5-Bromo-2H-indol-3-yl) ethyl] -propylamino] propyl] -1- (4-fluorophenyl) -1, 3-dihydro-i s oben zof ur an - 5 - ca rboni trilo (13o): LC / MS (m / z) 560 (MH *), Rt = 4.62, purity: 96%. 1- [3- [[3- (lH-lndol-3-yl) propyl] (2-phenoxy-ethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydro- i s ob in z o f u r an - 5 - c a rb on i t r i 1 (13 p): LC / MS (m / z) 574 (MH *), R t = 4.78, purity: 93%. 1- [3- [[2- (5-Methyl-lff-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1, 3 -dihi dr oi s oben zof ur an- 5-ca rboni tri 1 or (13q): LC / MS (m / z) 574 (MH *), R t = 4.82, purity: 93%. 1- t 3- [[2- (5 -Fluoro-Iff-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydrois obenz or furan-5-ca rboni tri 1 o ( 13r): LC / MS (m / z) 578 (MH *), Rt = 4.71, purity: 95%, 1- [3- [[3- (lH-Pyrrolo [3,2-] quinolin-3-] il) -propyl] (2-furylmethyl) amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (13s): LC / MS (m / z) 585 (MH * ), Rt = 3.60, purity: 90% 1- [3- [[3- (5-Methyl-2 H -indol-3-yl) propyl] (2-phenoxyethyl) amino] propyl] -1- (4 -fluorophenyl) -1, 3 -dihi dr oi s obenz of ur an - 5 - charcoal itri 1 or (13t): LC / MS (m / z) 588 (MH *), Rt = 4.96, purity: 82%. 1- [3- [[3- (5-Fluoro-2H-indol-3-yl) propyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1, 3-dihydroi s obenz of uran- 5 -carboni trilo (13u): LC / MS (m / z) 592 (MH *), R t = 4.82. Purity: 90%. 1- [3- [[2- (5,7-Difluoro-2-indol-3-yl) ethyl] - (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1, 3- di hi dr ois oben z o f ur an- 5 - ca rboni t r i 1 (13v): LC / MS (m / z) 596 (MH *), Rt = 4.84. purity: 92% e 1 - [3 - [[4- (lH-Pyrrolo [3,2-] quinolin-3-yl) -butyl] (2-furylmethyl) amino] propyl] -1- (4-f luorof enyl) -1, 3 -dihi dr oi s obenz of ur an - 5 - ca rbon itr ilo (13w): LC / MS (m / z) 599 (MH *), Rt = 3.71. purity: 83%. 1- [3- [(2-Phenoxyethyl) [2- [5- (2-propyl) -1 H -indol-3-yl] ethyl] amino] propyl] -1- (4-fluorophenyl) -1, 3 -dihi dr oi s oben zof ur an- 5 - c arboni tri 1 or (13x): LC / MS (m / z) 602 (MH *), R t = 5.24. purity: 78%. l- [3- [[2- (5-Bromo-l- "- indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-f-chlorophenyl) -1,3-dihi dr oi s oben zof ur an- 5-ca rboni tri 1 or (13y): LC / MS (m / z) 6388 (MH *), R t = 4.98, purity: 91%.

Example 14 1- (3-Iodopropyl) -1- (4-fluorophenyl) -1, 3 -dihi dr oi s obenz or f u r an- 5-carboni t r i 1 co (14a). A solution / s uspen s ion of 1 - (3-cl or opr opi 1) - 1 - (4-fluorophenyl) dihydroisob in zofuran-5-carbonitrile (20 g, 35 mmol, 80% pure) and sodium iodide ( 285 g, 1.9 mol) in dry acetone (200 mL) was heated at reflux for 24 h. The mixture was evaporated, and fractionated between ether and water. The ether layer was separated and washed successively with water and brine.

The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated, to give 1- (3-hydropropyl) -1,3-dihydroisobenzofuran-5-carbo-nitrile (25.8 g, 99%, 80% pure) as a thick oil 1 H NMR (CDC13) d 1.6-1.9 (m, 2H), 2.21 (ddd, 1H), 2.31 (ddd, 1H), 3.16 (td, 2H), 5.12 (dt, 1H), 5.21 (dt, 1H), 7.02 (t, 2H) 7.41 (d, 2H), 7.43 (d, 1H), 7.51 (s, 1H), 7.62 (dq, 1H). The following compounds were prepared analogously: 1- (2-Yodoethyl) -1- (-fluorophenyl) -1, 3-dihi dr oi s oben zof uran-5-ca rbon itri 1 o (14b) yellow oil, LH NMR (CDCl 3) d 2.4-2.9 (m, 2H), 3.38 (dt, 1H), 3.46 (dt, lH), 5.15 (d, 1H), 5.21 (d, 1H), 7.03 (t, 2H) , 7.35-7.48 (m, 3H), 7.52 (s, 1H), 7.62 (d, 1H), 7.03 (t, 2H), 7.35-7.48 (m, 3H), 7.52 (s, 1H), 7.62 (d , 1 HOUR) . 1- (4-iodobutyl) -1- (4-fluorophenyl) -1,3-dihydrois obenzo furan-5-carboni trilo (14c): yellow oil, 1 R NMR (CDCl 3) d 1.1-1.5 (m, 2H), 1.81 (tt, 2H), 2.00-2.30 (m, 2H), 3.11 (t, 2H), 5.14 (d, 1H), 5.20 (d, 1H), 7.01 (t, 2H), 7.35-7.47 (m, 3H), 7.51 (s, 1H), 7.60 (d, 1H).

Example 15 1- (3- (Ethylamino) propyl) -1- (4-fluorophenyl) -1,3-dihydric acid or 5-cathbonic acid (15a). To a stirred solution of 1- (3-iodopr opyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12.9 g, 30 mmol, 8% pure) in ethanol (15 (one Ethylamine solution (20.3 g, 450 mmol) in THF (50 mL) portions was added, and the mixture was stirred overnight.The solution was evaporated di so 1 vi / o suspended in water.The pH was adjusted to 12 using solution of aqueous sodium hydroxide (2M) and extracted with ether The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil.This oil was purified by silica chromatography using 50% v / v ethyl acetate / heptane as eluent, followed by 10% v / v triethylamine 40% v / v ethyl acetate / heptane, followed by 20% v / vtr ie ti 1 amine / ethyl acetate to give the title compound (5.52 g, 57%) as a pale yellow oil.1H NMR (CDC13) d 1.05 (t, 3H), 1.2-1.6 (m, 2H), 2.15 (ddd, 1H), 2.24 (ddd) , 1H), 2.57 (q, 2H ), 2.58 (t, 2H), 5.12 (dt, 1H), 5.20 (dt, 1H), 7.00 (t, 2H), 7.38 (d, 1H), 7.42 (dd, 2H), 7.49 (s, lH) , 7.58 (ddt, 1H).

The following compounds were prepared analogously: 1- (2- (Methylamino) ethyl) -1- (4-fluorophenyl) -1,3-dihydric acid soben zof ur an-5-ca rboni tr il (15b ): yellow oil; 1 H NMR (CDC13) d 2.38 (s, 3H), 2.33-2.72 4H), 5.13 (d, 1H), 5.20 (d, 1H), 7.01 (t, 2H), 7.37-7.47 (m, 3H), 7.5- (s, 1H), 7.59 (d, 1H). 1- (4- (Methylamino) butyl) -1- (4-fluorophenyl) -1,3-dihydr oi s oben z or furan- 5-ca rboni t r il o (15c): 'The yellow oil; 1 E NMR (CDC13) d 1.00-1.45 (m, 2H), 1.46 (tt, 2H), 2.10 (ddd, 1H), 2.21 (ddd, 1H), 2.37 (s, 3H), 2.50 (t, 2H) , 5.13 (d, 1H), 5.19 (d, 1H), 7.00 (t, 2H), 7.34-7.46 (, 3H), 7.49 (s, 1H), 7.59 (d, 1H). 15 Pharmacological Evaluation The affinity of the compounds of the invention to 5-HT? A receptors was determined by measuring the binding inhibition of a ligand. radioactive in 5-HTiA receptors, as described in the following test: Inhibition of the 3H-5-CT Link to Human 5? A Receptors By this method the inhibition by the 5-HTiA binding agents of the 3H-5-carboxamido-3-carboxamido-3H-5-CT agonist 5-HT receptors for stably cloned humans expressed in transfected HeLa cells (HA7) was determined in vitro. (Fargin, et al, J. Biol. Chem., 1989, 264, 14848. The test was carried out as a modification of the method described by Harrington, MA et al, J. Pharmacol. Exp. Ther., 1994, 268, 1098 Human 5-HT ?A receptors (40 μg of cell homogenate) were incubated for 15 minutes at 37 ° C in 50 mM Tris buffer at pH 7.7 in the presence of 3H-5-CT. μM of methyl ether The reaction was determined by rapid filtration through Unifilter GF / B filters in a Tomtec Cell Harvester The filters were counted in a Packard Top Counter The results obtained are presented in Table 1 below. The invention was also tested for its effect on a reabsorption of Rotonine in the following test: Inhibition of Absorption? -5-H_ in Rat Brain Synaptosomes Using this method, the ability of the drug to inhibit the accumulation of 3H-5-HT in whole rat brain synaptosomes was determined in vitro. The test is carried out as described by Hyttel, J., Psychopharmacology 1978, 60, 13. The results obtained are presented in Table 1: Table 1 Table 1 ^ reference compounds In addition, the antagonistic activity of 5-HT [alpha] A of some compounds of the invention has been estimated in vitro at stably cloned 5-HT [alpha] A receptors expressed in transfected HeLa cells (HA7). In this test, the antagonistic activity of 5-HT? A is estimated by measuring the ability of the compounds to antagonize the inhibition induced by 5-HT, of the accumulation of cAMP induced by forskolin. The test was carried out as a modification of the method described by Pau els, P.J. et al, Biochem Pharmacol.-, 1993, 45. 375.

As seen from the above, the compounds of the invention showed affinity for the 5-HT? A receptor. In addition, many of the compounds of the present invention possess valuable activity as replenished serotonin inhibitors. Accordingly, the compounds are considered useful for the treatment of psychiatric and neurological disorders as mentioned above.

Pharmaceutical Formulation The pharmaceutical formulations of the invention can be prepared by conventional methods in the art. For example: tablets can be prepared by mixing the active ingredient with common adjuvants and / or diluents and subsequently compressing the mixture in a conventional tablet machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive commonly used for such purposes, such as colorants, can be used. flavorings, preservatives, etc. , as long as they are compatible with the active ingredients. Solutions for injections can be prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably in sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling in suitable ampoules or flasks. You can add any-. suitable additive conventionally used in the art, such as tonicity agents, preservatives, an t i oxy t t e s, etc. The pharmaceutical compositions of the invention, or those that are made according to this invention, can be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, syrups, etc., or for a lighter. you in the form of solutions for injection. To prepare such compositions, methods well known in the art can be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art can be used. Conveniently, the compounds of the invention are administered in dosage form unit containing compounds, in an amount of about 0.01 to 1000 mg. The total daily dose is usually in the range of about 0.05-500 mg, and more preferably from about 0.1 to 50 mg of the active compound of the invention.

Claims (35)

1. An i s ob z o f u r an o that has the Formula wherein R is hydrogen, halogen, trifluoromethyl, t r i f 1 uo r ome t i 1 ul ul oni 1 oxy, C6_6 alkyl / C2_6 alkenyl, C2_6 alkynyl. C3-a cycloalkyl. C6-6 alkoxy, hydroxy, formyl, acyl, amino, Cj-6 alkylamino, C2_2-dialkylamino, acylamino, C-6-aminoca bonylamino alkoxycarbonylamino, at 1 qui 1 ami noca rboni 1 amino C ? -6, tell 1 qui no ca rbon i 1 ami of C2-? 2, nitro, cyano, COOH, or COO-alkyl of C i_ 6; R2 and R3 are each independently selected from hydrogen, trifluoromethyl, Ci-e alkyl, C2_6 alkenyl. C2_6 alkynyl. C3-8 cycloalkyl and C 1 6 alkoxy; n is 1,2,3,4 or 5; m is O or 1; A is selected from the following groups: where Z is O or S; s is 0 or 1; q is 0 or 1; R 4 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl. Ci-e-Aryl alkyl, or C? _-O-Al-alkyl aryl, D is a spacer group selected from the straight or branched alkylene chain of C i -e and alkenylene of C2_6, C2_ alkynylene; B is a group selected from a group of formula (II), (III) and (IV) («D (IV) wherein R5, R6, R7, R8, R9, and R10, are each independently selected from the substituents R1; R8 and R9 together form a ring of optionally fused 5 or 6 members further containing heteroatoms; and the resulting heterocycle optionally substituted with substituents selected from those substituted for R1; or two of the groups of R.sup.5, R.sup.6, and R.sup.7 are joined together to form a tan-O- (CH.sub.2) p-O-, where p is 1 or 2; Ar and Aryl are independently selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl or, 1-indolyl, 2-indolyl 3-indolyl, indo 1 - 2-on-1-i 1 or, indol-2-on-3-i 1 or, 2- or 3-benz or fur ani 1 or, 2- or 3-benzotiofeni 1 or, 1-naphthyl or 2 -naphthyl, each optionally substituted with halogen, C? -6 alkyl. C6-C6 alkoxy, C-β alkylthio, hydroxy, Ci-g alkylsulfonyl, cyano, trifluoromethyl, tri-fluorine, useful fonoxy, C3_8 cycloalkyl. cycloalkyl of C 3-8 - a 1 qu i 1 of Ci-e, nitro, amino, Ci-e alkylamino, C2_2 dialkylamino, acylamino or alkylenedioxy; its enantiomers and pharmaceutically acceptable acid addition salt of the same

2. A compound of claim 1, characterized in that A is a group of formula I.

3. A compound of claim 1, characterized in that A is a group of the formula II.

4. A compound of claim 1, characterized in that A is a group of the formula III.

5. A compound of claim 1, characterized in that A is a group of the formula IV.

6. A compound of claim 2, characterized in that R 4 is methyl, ethyl, propyl, 2-propen-1-yl, 2-f-urylmethyl, 2-phenoxyethyl;

7. A compound of any of claims 2 and 6, characterized in that q = 0;

8. A compound of any of claims 2 and 6, characterized in that q = l and Z is O.

9. A compound of any of claims 1-8, characterized in that B is a group of formula II.

10. A compound of any of claims 1-8, characterized in that B is a group of formula III.

11. A compound of any of claims 1-8, characterized in that B is a group of formula IV.

12. A compound of claim 9, characterized in that at least one of R5, R6 and R7 is me t oxy.

13. A compound of claim 9, characterized in that Formula II is a benzodioxane group or a 1,2-methyl-1-endyloxybenzene group.

14. A compound of claim 10, characterized in that Formula III is a 3-indole.

15. A compound of claim 14, characterized in that the 3-indolyl is substituted at the 5-methyl, fluoro, chloro, bromo, iodo, t-butyl or i-propyl position, or at the 7-position with fluoro, chloro or carboxy; or disubstituted by 5,7-difluoro, 4-f 1 or o-7 -me t i 1 o or 4-cl or r o -7-me t i 1 o, or the two substituents together form a pyridyl ring fused to 3-indolyl.

16. A compound of claim 11, characterized in that Formula IV is a 4-indolyl group or a 5-indolyl group.

17. A compound of any of claims 1-16, characterized in that Ar is phenyl or phenyl substituted with halogen or CF3;

18. A compound of claim 17, characterized in that Ar is phenyl which can be substituted with Cl or F in the 4 position or Cl or CF3 in the 3 position.

19. A compound of any of claims 1-18, characterized in that R1 is H, CN or F at the 5 position of the group i s oben z or fu rano.

A compound of any of claims 1-19, characterized in that R2 and R3 are selected from hydrogen or methyl.

21. A compound of any of claims 1-20, characterized in that n = 2, 3 or 4.

22. A compound of claim 21, characterized in that n = 3;

23. A compound of any of claims 1-22, characterized in that m = 0.

24. A compound of any of claims 1, 18, 19, 20, 21, and 23, characterized in that R2 and R3 are both hydrogen; R1 is H, CN or F at position 5 of the isobenzofuran group; and Ar is phenyl which can be substituted with F or Cl in the 4-position or with Cl or CF3 in the 3-position.

25. A compound of any of claims 1 and 24, characterized in that A is a group of the formula I; q = 0; R4 is methyl; D is propylene; m = 0 and B is a 1,4-benzodioxane group of Formula II attached at position 5.

26. A compound of any of claims 1 and 24, characterized in that A is a group of the formula I; R4 is CH3 or prsp-2-en-l-yl; n = 3; D is ethylene or propylene; and B is a phenyl group wherein at least one substituent is OMe.

27. A compound of any of claims 1 and 24, characterized in that A is a group of the formula I; q is 0; R 4 is methyl, ethyl, propyl, 2-p-1-phenyl, 2-phenyl or 2-phenoxyethyl; D is ethylene or propylene; m = 0; and B is a 3-indolyl group of Formula III.

28. A compound according to the rei indication 27, characterized in that the 3-indolyl group is substituted with methyl, fluoro, chloro, bromo, iodo, t-butyl or i-propyl at the 5-position; or fluoro, chloro or carboxy in the 7-position; or with 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro-7-methyl; or the two substituents together form a pyridyl ring fused to the 3-indolyl group.

29. A compound of any of claims 1 and 24, characterized in that A is a group of the formula II or III; n = 3; m = 0; and B is a 4- 5-indolyl group of Formula IV wherein R 10 is hydrogen; R1 is CN at position 5 of the obenz o fur ano and Ar is 4 - Fluo r o f at i 1 o.

30. The compound according to claim 1, which is (-) - 1 - [3 - [[4 - (1, 4 - Benzodioxan-5-yl) butyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-ca rboni tri 1 o, oxalate of 1 - [3 - [[3 - (1, 4 - B in z odi oxan-5-yl) propyl] methylamino] propyl] -1- (4-f luorophenyl) -1, 3 - di hi dr oi s obenz of ur an- 5 - ca rbon itri 1, oxalate from l- [3- [[2- (1,4-Benzodioxan-5-yl) ethyl] methylamino] -propyl] -1- (4-fluorofenyl) -1,3-dihydroisobenzofuran-5-carbonyl tri lo, oxalate of 1 - [3 - [[1,4-B in z odi oxan-5-ylmethyl] methylamino] propyl] -1- (4-fluorophenyl) -1, 3 -dih i dr ois oben zof ur an - 5 -ca rboni tri 1 o, l- (4- Fluorophenyl) -1- [3- [4- (2-methoxyphenyl) -piperazinyl] -propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1 - (4 - Fluorophenyl) -1- [3- [methyl- [2- (2-methoxy-phenoxy) e't]] amino] propyl] -1,3-dihydroisobenzofuran-5-carbonyl trile, 1- (4-Fluor of enyl) 1) - 1 - [3 - [me ti 1 [2 - (3-methoxy-phenoxy) ethyl] amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, (S) -1- [3- [[4 - (li? -Indol-3-yl) butyl] methyl-amy]] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5-carbonitrile, '1 - [3 - [ [4 - (1 H-1 ndo 1 -3-yl) butyl] methylamino] -propyl] -1-phenyl-1,3-dihydroisobenzofuran, (S) -1 - [3 - [[3- (l-i-Indole -3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[3- (1 H-Indol-3-yl) propyl] ] methylamino] propyl] -l-phenyl-l, 3- dihydroisobenzofuran, 5- [3 - [[3- (l-Phenyl-1,3-dihydroisobenzofuran-1-yl) propyl] methylamino] propyl] -1,4-benzodioxane, 5 - [3 - [[3- [1 - (3-Chlorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] methylamino 'pr op i 1] - 1,4-benz odi oxano, 5 - [3 - [[3 - [1 - (4 - Fluorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] -methylamino] propyl] -1,4-benzodioxane, 5- [3- [[3- [1- (3-triflu 1 -o-rome-phenyl) ) -1, 3-dihi dr oi sobenzofuran-1-yl] propyl] methylamino] propyl] -1,4-benzodioxane, 1- [3 - [[3- (1,4-Benzodioxan-5-yl) propyl] methylamino] propyl] -1- (4-chlorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [4- (l-l-Indol-4-yl) piperazinyl] propyl] -1- (4- fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [4- (1 H-Indol-3-yl) piperidinyl] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile, 5- [3- [[3- [-5-Fluoro-1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] methylamino] propyl] -1,4-benzodioxane , 1 - [3- [[2- (lf f-Indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-fluorophenyl) -l- [3 - [[2- (3-methoxyphenyl) ethyl] methylamino] propyl] -1,3-dihydro-isobenzofuran-5-carbonitrile, 1- (4-fluorophenyl) -1 - [3- [[2- (3-methoxyphenyl) ethyl] (prop -2-en-l-yl) amino] -propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (-Fluorophenyl) -1- [3- [[2- (2-methoxyphenyl) ethyl] (prop-2-en-l-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [ 3- [[2- (2, 5-Dimethoxyphenyl) ethyl] methyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-furan-5-carbonitrile, t l- [3- [ [2- (2,5-Dimethoxyphenyl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4) -Fluorophenyl) -l- [3- [[2-phenoxyethyl] methylamino] propyl] -1,3-dihydroisobenzo-furan-carbonitrile, 1- [3- [[2- (li? -Indolyl-3-yl) ethyl] ] - (prop-2-en-l-yl) amino] propyl] -1- (4-fluorofenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluoro-phenyl) -1- [ 3- [[2-phenoxyethyl] (prop-2-en-l-yl) amino] -propyl] -1,3-dihydroisobenzofuran-5-carbo trilel, 1 • (4-Fluorophenyl) -1- [3- [[3- (2-methoxyphenyl) propyl] -methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-fluorophenyl) -1- [3- [[3- (2-methoxyphenyl) propyl] ] (prop-2-en-l-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-ca rsnitrile, 1- (4-Fluo rof eni 1) - 1 - [3 - [[3 - (3 -me t oxy f eni 1) pr opi 1] (prop-2-en-l-yl) amino] propyl ] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-fluorophenyl) -1- [3- [[3- (2-methoxy-phenoxy) propyl] methylamino] propyl-1,3-dihydroisobenzo-furan- 5-carbonitrile, 1- (4-Fluorophenyl) -1- [3- [[3- (2-me t ox if in oxy) pr op i 1] (pr op - 2 - en - 1 - i 1) ami no] pr op i 1] - l, 3-dihydroisobenzofuran-5-carbonitrile, 1- (4 Fluorophenyl) -1- [3- [[3- (3-methoxyphenoxy) propyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-fluorophenyl) -l- [3 - [[3 - (3 me t oxi phenoxy) p rop i 1] (prop- 2 -en- 1 - i 1) amino] pr op i 1] -1, 3 -di hi dr ois oben zo f uran- 5 - ca rboni tri 1 o, l- [3- [(2-Benzyloxyethyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [(2-benzyloxyethyl) propri- 2-en-l-yl) amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [3 - [[3- (l-indolyl-3-yl) propyl] (prop-2-en-l-yl) amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 [3 - [[3 - (1 H- Indolyl-3-yl) propyl] (2-propynyl) amino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [3 - [[3- (li- -Indolyl-3-yl) propyl] methylamino] propyl] -1- (4-fluorofenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[2- (5'-Methyl-lf-indole -3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -I, 3-dihydroisobenzofuran-5-carbonitrile, l- [3 - [[2- (7-Fluoro-lyo-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbonitrile, 5-Fluoro-l- [3 - [[3- (5-methyl-li-indol-3-yl) propyl] methylamino] -propyl] -1- (4-fluorophenyl-1, 3 -dihydroisobenzofuran, 5-Fluoro-l- [3- [[3- (7-fluoro-l - "- indal-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran, 1 - [3- [[3- (5-methyl-l-yl-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran, 1 - [3 - [[5 - Me ti 1 - 1 H -indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl [3 '(li? -indol-3-yl) propyl] amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 [3- [Ethyl [2- (5-methyl-lf- indol-3-yl) ethyljamino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [3- [[3- (7-Fluoro-li? -indol-3 -yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitri 1 _, l- [3- [[3- (5-Fluoro-lf-indol-3- il) propyl] methylamino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl [2- (5-f luoro-1-indol-3-yl ) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbon itryl, 1- [3- [Ethyl [2 • (7-fluoro-li? -indol-3-yl) ethyl] to inojpropyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile , l- [3- [[2- (5-Chloro-lH-indol-3-yl) ethyl] -acetylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroissenzofuran-5-carbonitrile, 1- [3- [[3- (5 • Chloro-li? -indol-3-yl) propyl] methylamino] propyl] -5- fluoro-1- (4-fluorophenyl) -1,3-dihydroisobenzofuran, 1- [3- [[4- (5-Methyl-lH-indol-3-yl) butyl] methylamino] -propyl] -1- (4 -fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl [3- (5-methyl-lJI-indol-3-yl) propyl] amino] propyl] -l- (4-fluoro f) eni 1) - 1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl [3 (7-f luoro-1-yl-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) ) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [3- [Ethyl [3- (5-fluoro-lff-indol-3-yl) rovyl] amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[3- (5-chloro-lido-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbonitrile, l- [3- [[2- (7-Chloro-lH-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-f luorofenyl) -1,3-dihydroxy s "? benzofuran-5-carbonitrile, 1 - [3 - [[2- (5 • Chloro-li? -indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1, 3- dihydroisobenzofuran-5-ca rbon itrilo, l- [3- [[2- (5,7-Difluoro- lH-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[4- (5-Fluoro-lf-indole -3-yl) butyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [3- [[4- (5-Chloro-lH-indol-3 -yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1, 3- dihydroisobenzofuran-5-carbonitrile, 1- [3- [[3- (5'-chloro-lf-indol-3-yl) -propyl] -ethylamino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 -carbonitrile, 1- [3- [[3- (5,7-Diflouro-lJ? -indol-3-yl) propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 -carbonitrile, 1- [3- [[2- (5-Bromo-li? -indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile , l- [3- [[3- (5-Bromo-lH-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[2- (5-Bromo-lJ? -indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[4- (5-Bromo-12? -indol-3-yl) util] (me ti 1-amino] propyl] -1- (-fluoro-f-1) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[3- (5-Bromo-lly-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [ 3- [Ethyl [2- (5-iodo-lH-indol-3-yl) e useful] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl [3 - (5-iodo-1 - "- indol-3-yl ) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [2- [[4- (5-Chloro-lH-indol-3-yl) butyl] methylamino] ethyl] -1- (4-fluorophenyl) -1, 3- dihydroisobenzofuran-5-carbonitrile, 1- [2- [[4-5-Bromo-li? -indol-3-yl] butyl] methylamino] ethyl] -1- (4-fluorophenyl)), 3-dihydroisobenzofuran-5-carbonitriio, 1 - [4 - [[2- (5,7-Difluoro-lff-indolyl) ethyl] -methylamino] butyl] -1- (4-fluorofenyl) -1, 3 -dihydroisobenzofuran-5-carbonitrile, 1- [4- [[2-7-Chloro-lf-indol-3-yl] ethyl] -methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile, l- [4 - [[2- (5-Chloro-li? -indol-3-yl) ethyl] methylamino] butyl] -1- (4-f luorofenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile, 1- [4- [[2-Bromo-lly-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [4 - [[2- (5-Methyl-lly-indolyl) ethyl] methylamino] butyl] -1- (4-fluorofenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4- [[ 2 -5-Iodo-lH-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4 - [[2- (5 -t-Butyl-lH-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4- [[2- (5 - 1 Propyl-li? -indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [3 - [[2- [5-Methyl-li? -indolyl) ethyl] prop-2-en-yl] amino ] propyl] -1- (4-fluoro- phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 - [3- [[2- (lH-indol-3-yl) ethyl] (prop-2-en-l-yl) amino] propyl] -1 - (4-fluorophenyl) -1, 3-dihydro-i s or nzofuran-5-carbonitrile, 1- [3- [[2- (7-Fluoro-lü-i ndol-3 -i 1) eti 1] (prop-2-en-1-yl-) amino] propi 1] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, l- [3 - [[3- (5-Fluoro- l - "- indol-3-yl) propyl] (prop-2-en-l-yl) amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzo furan-5-carbonyl trile, - [3 - [[3 - (7-Fl uor or - 1 H- indol-3-yl) propyl] (prop-2-en-l-yl) amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, l- [3 - [[2- (5-chloro-lH-indol-3-yl) ethyl] (prop-2-en-l-yl) amino] propyl] - 1- (4-fluoro-f-enyl) - 1, 3 - di hi dr oi s oben zof ur an- 5 - ca rbon itri 1 o, 1- [3 - [[2- (5,7-Difluoro-li β-indol-3-yl) ethyl] -propyl-aminojpropyl] -1- (4-fluorophenyl) -1,3-dihydroiso-benzofuran-5-carbonitrile, 1- [3- [[2- [5 (2- propyl) - 1 H-indol-3-yl) ethyl] (- 2-propylamino] propyl] -1- (4-fluorophenyl-1,3-dihydroisobenzofuran-5-carbonitrile, l- [3 - [[3- (4-Fluoro-7-methyl-li-indol-3-yl ) propyl] - (prop-2-en-l-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 - [3 - [[2- (4 - chloro-7-methyl-li? -indol-3-yl) ethyl] (prop-2-en-l-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroiso- benzofuran-5-carbonitrile, 1 - [3 - [[3- (5-chloro-li? -indol-3-ii.}. propyl] (prop-2-en-l-yl) amino] propyl] - 1 - (4-fluorofenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[2- (5-Pyrrolo [3,2] -h] -li? -quinolin-3-yl) ethyl] ( pr op-2-en- 1 - i 1) ami no] pr opi 1] - 1 - (4-f luo-ro-phenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile, 1 - [3- [[3 - (7-Fluoro-l-indol-3-yl) ropil] (2-furylmethyl) aminsjpropyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[ 4- (7-Cartoxy-1 H- indol-3-i 1) bu ti 1] (prop-2-en-l-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbonitrile, 1- [3- [[2- [5-Bromo-lH-indol-3-yl] ethyl] propylamino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5- carboni trilo, 1 - [3 - [[3 - (1 H- i ndo 1 - 3-yl) pr op i 1] 2-phenoxyethyl) amins] propyl] -1- (4-f luorophenyl) - 1, 3 -dihydroisobenzofuran-5-carbonitrile, 1- [3- [[2- (5-ethyl-lH-indol-3-yl) ethyl] (2-phen oxyethyl) amino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroissenzofuran-5-carbonitrile, 1 - [3 - [[2 - (5-Fl uo ro-1 H- i nd 1 - 3 -yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 - [3- [p- (5-pyrrolo [3, 2-h] -l-quinolin-3-yl) propyl] -2-furylmethylamino or] ropil] -1- (4-fluorophenyl) -1, 3 -dihydr oi s oben zo fur an- 5-ca rboni tri 1 o, l- [3 - [[3- (5- Methyl-li-indol-3-yl) propyl] (2-f-enoxyethyl) amino] -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [[ 3- (5-Fluro-lJI-indol-3-yl) propyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 - [ 3- [[2- (5y 7-Difluoro-lif-i-_dol-3-yl) ethyl] (2-phenoxy-ethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydro- isobenzofuran-5-carbonitrile, l- [3- [[4- (5- Pyrrolo [3, 2-h] -lfl-quinolin-3-yl) butyl] -2-fu omethylamino] propyl] -1- ( 4-f-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 - [3 - [2-phenoxyethyl] [2- [5- (2-propyl) -lH-indol-3-yl] ethyl] -amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzo-f uran-5-carbon i tri 1 oo 1 - [3 - [[2 - (5-B rino- 1 H- i ndo 1 - 3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, or an acid addition salt thereof.

31. A pharmaceutical composition comprising a compound according to claims 1 to 30, or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent. íai

32. The use of a compound according to claims 1 to 30, or pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of a disorder or disease responsive to the effect of 5-HT receptors. ?TO.

33. The use of a compound according to claim 32, wherein the medicament is for the treatment of depression, psychosis, disorders with anxiety, panic disorder, obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischemia, senile dementia, cardiovascular disorders and social phobia.

34. A method for the treatment of a disorder or disease of the living animal body, including a human, that responds to the effect of 5-HT? A receptors, which comprises administering to such a living animal body, including a human, a therapeutically effective amount of a compound according to claims 1 to 30, or a pharmaceutically acceptable acid addition salt thereof.

35. A method of treatment according to claim 34, wherein a disorder or disease is depression, psychosis, anxiety disorders, panic disorder, obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischemia. , dementia senii, cardiovascular disorders and social phobia.