SK7762001A3 - Benzofuran derivatives, their preparation and use - Google Patents

Description

Technical field

The present invention relates to novel benzofuran derivatives strongly binding to

5-HT1A receptor, pharmaceutical compositions containing these substances and their use in the treatment of certain psychiatric and neurological disorders. Many of these compounds of the invention are also potent serotonin reuptake inhibitors and are considered to be particularly useful for the treatment of depression.

BACKGROUND OF THE INVENTION

Clinical studies of known 5-HT 1A agonists such as buspirone, ipsapirone and gepirone have shown that 5-HT 1A agonists are useful for the treatment of anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder (Glitz) , D.

A., Pohli, K., Drugs 1991, 41, 11). Preclinical studies indicate that total agonists are also useful for the treatment of the above-mentioned anxiety disorders (Schipper, Human Psychopharm., 1991, 6, S53).

There is also clinical and preclinical evidence supporting the beneficial effect of 5HT 1A partial agonists on the treatment of depression as well as impulsive disorders and alcohol control (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; Graf et al., Int Clin Psychopharmacol 1993, 8 , 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).

5-HT1A agonists and partial agonists inhibit isolation-induced aggression in male mice, suggesting that these agents are useful in the treatment of aggression (Sanchéz et al., Psychopharmacology, 1993, 110, 53-59).

It was further reported that 5-HT 1A agonists exhibit activity in animal models predictive of antipsychotic effects (Wadenberg and Ahlenius, J Neural Transm., 1991, 83, 43; Ahlenius, Pharmacol & Toxicol, 1989, 64, 64). ·· ··

-23; 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 may therefore be useful for the treatment of psychotic disorders such as schizophrenia. Recent studies also suggest that 5-HT1A receptors are important in serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609), indicating that 5-HT1A agonists are useful for treating side effects induced by conventional antipsychotic agents such as for example haloperidol.

5-HT 1A agonists have shown neuroprotective properties of focal and general cerebral ischemia in rodent models and may therefore be useful in the treatment of ischemic disease states (Prehn, Eur. J Pharm. 1991, 203, 213).

Pharmacological studies have been presented suggesting that 5-HT 1A antagonists are useful for the treatment of age dementia (Bowen et al., Trends New. Sci. 1992, 15, 84).

A review of 5-HT 1A antagonists and proposed potential therapeutic targets for these antagonists based on preclinical and clinical data is provided in Schechter et al., Serotonin, 1997, Vol. It has been reported that 5-HT 1A antagonists may be useful for the treatment of schizophrenia, dementia associated with Alzheimer's disease and, in conjunction with SSRI antidepressants, may also be useful for the treatment of depression.

Both in animal models and in clinical trials, 5HT1A agonists have been shown to have antihypertensive effects via a central mechanism (Saxena and Villalon, Trends Pharm. Sci. 1990, 11, 95; Gillis et al., J Pharm. Exp. Ther. 1989, 248, 851). 5-HT 1A ligands may therefore be useful for the treatment of cardiovascular disorders.

5-HT reuptake inhibitors are well known antidepressant drugs and are useful for the treatment of panic disorders and social phobia.

The effect of combined administration of a compound that inhibits serotonin reuptake and antagonist of _{5-HT-receptor} has been evaluated in several studies (Innis, RB et al., Eur J Pharmacol, 1987, 143, p 195-204 and Gartside,

S.E., Br. J Pharmacol 1995, 115, p 1064-1070, Blier, P. et al., Trends Pharmacot Sci. 1994, 15,220). In these studies it was found that antagonists ·· ···· · ·

5-HT1A receptors could remove the initial arrest of 5-HT neurotransmission induced by serotonin reuptake inhibitors and thus cause immediate enhancement of 5-HT transmission and a faster onset of therapeutic action.

Several patent applications have been filed covering the use of a combination of a 5-HT 1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A2-714 663).

Accordingly, agents acting at the 5-HT 1A receptor, both agonists and antagonists, are considered to be of potential potential use in the therapy of psychiatric and neurological disorders and are therefore highly desirable. In addition, antagonists that also have potent serotonin reuptake inhibitory activity may be useful in the treatment of depression.

It has now been found that substances of a certain class of benzofuran derivatives bind to the 5-HT 1A receptor with high affinities. Furthermore, many of these compounds have been found to have potent serotonin reuptake inhibitory activity.

SUMMARY OF THE INVENTION

The present invention provides isobenzofuran derivatives of formula (I)

where

R ¹ is hydrogen, halogen, trifluoromethyl, trifluoromethylsulfonyloxy, C ₆ -alkyl, C ₂ -6alkenyl, C ₂ -6-alkynyl, C3-8-cycloalkyl, Ci-6-alkoxy, hydroxy, formyl, acyl, amino, C 6-alkylamino, C 2-12 -dialkylamino, acylamino, C 1-6 -alkoxycarbonylamino, aminocarbonylamino, C _1-6 -alkylaminocarbonylamino, C 2-12 -dialkylaminocarbonylamino, nitro, C 1-6 alkyl, COOH, or COOH;

R ² and R ³ are each independently selected from hydrogen, trifluoromethyl, C 1-6. ₆ -alkyl, C _{2nd 6} 'alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl and C 1-6 -alkoxy; n is 1, 2, 3, 4 or 5;

m is 0 or 1;

A is selected from the following groups:

R ⁴

I —n— (D) - (Z) - —N N—

(1)

where

Z is O or S;

s is 0 or 1;

q is 0 or 1;

R ⁴ is hydrogen, C 1-6 alkyl; _6- alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-Aryl, or C 1-6 -alkyl; _6- alkyl-OAryl,

D is a spacer group selected from branched or straight chains of C 1-6 alkylene, C 2-6 alkenylene and C 2-6 alkynylene;

B is a group selected from the group of formulas II, III, and IV

wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from R ¹ substituents; or R ⁸ and R ⁹ together form a fused 5- or 6-membered ring optionally containing additional heteroatoms;

or two of R ⁵ , R ⁶ and R ⁷ are bonded together to form a -O- (CH ₂ ) _p -O- bridge, wherein 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, 1-indolyl, 2-indolyl, 3-indolyl, indole-

2-one-1-yl, indol-2-one-3-yl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, ·· ····

1-naphthyl or 2-naphthyl, each of which is optionally substituted with halogen, C _1-6 alkyl, C 1-6 alkyl; _6- alkoxy, Ci. _6- alkylthio, hydroxyl, C 1-6 alkyl; _6- alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, C ₃ . _8- cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, nitro, amino, C1-6-alkylamino, C2-12-dialkylamino, acylamino or alkylenedioxy;

their enantiomers and their pharmaceutically acceptable acid addition salts.

In one embodiment of the invention A is a group of formula (1) and the other substituents are as defined above.

In another embodiment of the invention, A is a group of formula (2) and the other substituents are as defined above.

In a third embodiment of the invention A is a group of formula (3) and the other substituents are as defined above.

In a fourth embodiment of the invention A is a group of formula (4) and the other substituents are as defined above.

Thus, in a preferred embodiment of the invention A is a group of formula (1) and R ⁴ is methyl, ethyl, propyl, prop-2-en-1-yl, 2-furylmethyl or 2-phenoxyethyl; q = 0; or A is a group of formula (1) and Z is O and the other substituents are as defined above.

In another embodiment of the invention, B is a group of formula II, preferably an alkoxy-substituted phenyl, benzodioxane or 1,2-methylenedioxybenzene group and the other substituents are as defined above.

In another embodiment of the invention, B is a group of formula III, preferably a 3-indolyl group and the other substituents are as defined above.

In another embodiment of the invention, B is a group of formula III, preferably a 3-indolyl group, and R ⁸ and R ⁹ are preferably selected from hydrogen, methyl, fluorine, chlorine, bromine, iodine, tert-butyl or isopropyl at the 5-position; or fluorine, chlorine or carboxyl at the 7-position; or 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro-7-methyl; or the two substituents taken together form a pyridyl ring fused to 3-indolyl.

In another embodiment of the invention, B is a group of formula IV and the other substituents are as defined above.

Ar is preferably phenyl or phenyl substituted with halogen or CF ₃ , most preferably substituted with F or Cl at the 4-position or Cl or CF 3 at the 3-position.

R ¹ is preferably H, CN or F at the 5-position of the isobenzofuran group.

R ² and R ³ are preferably selected from hydrogen or methyl.

n is preferably 2, 3 or 4.

m is preferably 0.

In a preferred embodiment of the invention n = 2, 3 or 4; R ² and R ³ are both hydrogen; R ¹ is H, CN or F at the 5-position of the isobenzofuran group; and Ar is phenyl, which may be substituted with F or Cl at the 4-position or with Cl or CF ₃ at the 3-position, and the other substituents are as defined above.

In another preferred embodiment of the invention A is a group of formula (1); q = 0; R ⁴ is methyl; D is propylene; m = 0; and B is a 1,4-benzodioxane group of formula II attached at the 5-position and the other substituents are as defined above.

In another preferred embodiment of the invention A is a group of 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 are as defined above.

In another embodiment of the invention A is a group of formula (1); q is 0; R ⁴ is methyl, ethyl, propyl, 2-propen-1-yl, 2-furylmethyl or 2-phenoxyethyl; D is ethylene, propylene or butylene; m = 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 formula (2) or (3); n = 3; m = 0; and B is a 4- or 5-indolyl group of formula IV wherein R ¹⁰ is hydrogen; R ¹ is CN at the 5-position of isobenzofuran and Ar is 4-fluorophenyl and the other substituents are as defined above.

The invention also relates to a pharmaceutical composition comprising an isobenzofuran derivative 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 formula I or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of disorders or diseases susceptible to the action of 5-HT 1A receptors.

In particular, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of depression, psychosis, anxiety disorders, panic disorder, obsessive-compulsive disorder, impulsive control disorder, addiction alcohol, aggression, ischemia, senile dementia, cardiovascular disorders or social phobia.

In yet another embodiment, the invention relates to a method of treating a disorder or disease of an animal, including a human, that is sensitive to the effect of 5-HT 1A receptors comprising administering to such animals, including a human, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. .

The compounds of the invention have high affinity for the 5-HT _1A receptor. Accordingly, the compounds of the invention are considered useful for the treatment of depression, psychosis, anxiety disorders such as generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder, impulse control disorder, alcohol addiction, aggression, ischemia, senile dementia, cardiovascular disorders and social phobia.

Because of the combined 5-HT _1A receptor antagonism and inhibiting effect on serotonin reabsorption, many of the compounds of the present invention are considered to be particularly useful as medicaments for the treatment of depression with rapid onset of action. The agents may also be useful for treating depression in patients who are resistant to treatment with commonly available antidepressants.

Some of the compounds of Formula I may exist as optical isomers, and such optical isomers are also encompassed by the present invention.

The term C 1-6 -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-methyl-2-propyl and 2-methyl-1-propyl.

Similarly, C 2-6 -alkenyl and C 2-6 -alkynyl designate such groups having from two to six carbon atoms inclusive.

Halogen means fluorine, chlorine, bromine, or iodine.

The term C 3-8 -cycloalkyl refers to a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The terms C 1-6 -alkoxy, C 1-6 -alkoxy; _6- alkylthio, C _1-6 -alkylsulfonyl, refers to such groups in which the alkyl group is C 1-6 -alkyl as defined above.

Acyl means -CO-alkyl, wherein the alkyl group is C 1-6 alkyl. _6- alkyl as defined above.

Ci-6-alkylamino means -NH-alkyl, and C 2 is the _di-2-N - (- alkyl) _2, wherein alkyl is Ci-6-alkyl as defined above.

Acylamino means -NH-acyl, wherein acyl is as defined above.

C 1-6 -alkoxycarbonylamino means alkyl-O-CO-ΝΗ-, wherein the alkyl group is C 1-6 -alkyl as defined above.

C 1-6 -alkylaminocarbonylamino means alkyl-NH-CO-NH-, wherein the alkyl group is C 1 -C 6 -alkyl as defined above.

C ₂ .i ₂ dialkylaminocarbonylamino means (alkyl) ₂ -N-CO-NH- wherein the alkyl group is C-alkyl, as defined above.

Examples of organic acid addition salts of the present invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, mandelic, lactic, mandelic, malic, cinnamon, citracone, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic, as well as 8-halothiophylenes, for example with 8-bromothiophyline. Examples of the inorganic acid addition salts of the present invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.

In addition, the compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

Some of the compounds of the present invention contain chiral centers, and such compounds exist in the form of isomers (e.g., enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Racemic forms can be resolved into optical antipodes by known methods, for example by separating their diastereomeric salts with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for the optical resolution of racemates into optical antipodes is done by chromatography on an optically active matrix. Thus, the racemic compounds of the present invention can be resolved into their optical antipodes, for example by fractional crystallization of d- or I-salts (tartrates, almonds or camphorsulfonates). The compounds of the invention may also be optically resolved by formation of diastereomeric derivatives.

Other methods for resolving optical isomers known to those skilled in the art may be used. Such methods include those discussed in J. Jaques, A. Collet and S. Wilen in Enantiomrs, Racemates, and Resolutions'; John Wiley & Sons, New York (1981).

Optically active substances can also be prepared from optically active starting materials.

The isobenzofuran derivatives of the invention may be prepared by one of the following methods, including:

a) alkylating the amine of the formula

(V) wherein R ¹ , R ² , R ³ , R ⁴ , on Ar are as defined above with an alkylating agent of the formula G- (D) _S (Z) _q - (CH 2) mB-, wherein D, Z, m, s , q and B are as defined above and G is a suitable leaving group such as halogen, methylsulfonate or toluenesulfonate;

b) alkylating an amine of formula HA- (CH 2) _m -B, wherein A, m and B are as defined above with an alkylating agent of formula

(VI) ·· ······ · φ · • · φ · · · · · φ φ φ φ φ φ φ φ φ φ φ φ

- where R ¹ , R ² , R ³ , on Ar are as defined above and G is a suitable leaving group such as halogen, methylsulfonate or toluenesulfonate;

c) reductive alkylation of the amine of formula

(VII) wherein R ¹ , R ² , R ³ , R ⁴ , on Ar are as defined above with an aldehyde of formula

(VIII) wherein Z, m, q and B are as defined above and t is 1 to 5;

d) reducing the amide of the formula

(CH ₂₎ i (Z) - (CH ₂₎ -b (XI) wherein R ^1, R ^2, R ^3, R ^4, n, q, Ar, Z, m and B are as defined above and t is 1-5 ;

e) release of the final product by Hofmann elimination from the resin of the formula

R 2, R ³

R ⁴

-K

COOR '

(XII)

Ar (ch ₂ ) "(D) _s - (Z) - (CH ₂ ) - B ·· ····

··························

Wherein R ¹ , R ² , R ³ , R ⁴ , n, s, q, Ar, D, Z, m and B are as defined above, G is as defined above; and HOR 'is a hydroxy substituted resin, such as a cross-linked hydroxymethyl polystyrene resin or a Wang resin.

f) reacting a compound of formula

wherein R ¹ , R ² , R ³ , R ⁴ , Ar, D and N are as defined above; (OH 4 Q is a diol, such as a substituted ethylene glycol or propylene glycol, or a polymer-bound diol, with a hydrazine of the formula

wherein R ⁸ and R ⁹ are as defined above, using Lewis acids as catalyst.

Alkylations according to Methods a and b are generally carried out by boiling the reactants under reflux or heating them to constant temperature in a suitable solvent such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide or 1. methyl

2-pyrrolidinone in the presence of a base such as triethylamine or potassium carbonate. The amines of formula V are prepared by demethylation according to the method described by Bigler et al., Eur. J. Med. Chem. Chim. Ther, 1977, 12, 289-295, or by the methods shown in Examples 14 and 15. The starting materials used in Example 14 were prepared as described in Example 9 or from readily available materials using standard methods. The enantiomers of 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile used as starting material for demethylation are prepared as described in the EP patent

·· · · · · · · · · · · ·

no. 347,066th alkylating agents of formula G- (D) _s - (Z) _q - (CH ₂₎ m B are commercially available, prepared by methods conventional to chemists who are skilled in the art or are prepared as described in Examples 5 The ethyl 1, 4-benzodioxane-5-carboxylate used as the starting material in Example 5 is prepared by methods customary by chemists skilled in the art from the corresponding carboxylic acid prepared according to the literature (Fuson et al., J. Org. Chem., 1948, 13,489). alkylating agents of formula VI are prepared from the corresponding dimethylamine (formula VI: G = N (Me) ₂ ) as shown in the Example

9. Secondary amines of formula HA- (CH ₂ ) _m -B are commercially available, prepared using methods customary by chemists skilled in the art, or prepared according to literature procedures. 1- (2-Methoxyphenyl) piperazine is prepared according to Pollard et al., J. Org. Chem., 1958, 23, 1333. [2- (2-Methoxyphenoxy) ethyljmethylamine and [2- (3-methoxyphenoxy) ethyl] methylamine are prepared as described in Examples 7 and 10 using commercially available 2-methoxyphenoxyacetic acids. and

3-methoxyphenoxyacetate as starting materials.

Reductive alkylations according to c and d methods are performed according to standard literature methods using NaCNBI-h, NaBH ₄ or NaBH (OAc) 3 as a reducing agent in a suitable solvent.

The reductions of Methods e and f are generally carried out using LiAlH 4, AlH 3 or diborane in an inert solvent such as tetrahydrofuran, dioxane or diethyl ether at room temperature or at a slightly elevated temperature.

The release of the end products by Hofmann elimination in Method g is generally carried out using an organic base such as triethylamine or diisopropylethylamine in an aprotic organic solvent such as dichloromethane, toluene or N, N-dimethylformamide. The polymer of formula XII is prepared by a synthetic sequence as described in Example 4 and as described below. The starting acrylic ester resin (CH ₂ CHC (O) OR ') is prepared according to literature procedures (Brown et al., J. Am. Chem. Soc., 1997, 119, 3288-95) by acylating commercially available hydroxy-substituted resins such as for example cross-linked hydroxymethyl polystyrene or Wang resin with acryloyl chloride. Secondary amines of formula H ₂ NDZ- (CH ₂ ) _m -B are introduced by Michael ·· ····

-13 · ♦ 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 addition in an organic solvent such as N, N-dimethylformamide at room temperature. The secondary amines used are either commercially available, prepared by methods customary by chemists skilled in the art, or prepared according to literature procedures. 3- (2-Methoxyphenyl) propylamine is prepared according to Leeson et al., J. Med. Chem. 1988, 31, 37-54, 3- (3-methoxyphenyl) propylamine according to Meise et al. Liebigs Ann. Chem., 1987, 639-42, 3- (2-methoxyphenoxy) propylamine according to Augsev et al., J. Med. Chem., 1965, 8, 356-67,

3- (3-methoxyphenoxy) propylamine according to Bremner et al., Aust. J. Chem. 1984, 37, 129-41, 2-benzyloxyethylamine according to 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- (1H-indolyl-3-yl) propylamine according to Jackson et al., J. Am. Chem. Soc., 1930, 52, 5029. The second converting group is introduced by alkylation with an agent of formula VI by boiling the reactants under reflux or by heating them to constant temperature in a suitable solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, Λ. N, N-dimethylformamide, dimethylsulfoxide or

1-methyl-2-pyrrolidinone in the presence of a soluble base such as diisopropylethylamine or triethylamine, or by reductive alkylation with an aldehyde of formula IX using standard literary solid-phase synthesis methods using NaCNBhh, NaBH ₄ or NaBH (OAc) 3 as a reducing agent in a suitable solvent. A third variation group was introduced by quaternization using an alkylating agent of formula R ⁴ -G in an organic solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide or 1-methyl-2- pyrrolidinone at room temperature to provide resins of formula XII.

The indole formation of Method h is carried out by reacting acetals of formula XIII with arylhydrazines of formula XIV, resulting in the corresponding hydrazones, which are subsequently converted to indoles by Fischer indole synthesis. The synthesis sequence is preferably performed as a one-pot process using Lewis acid catalysts, preferably zinc chloride or boron trifluoride, or protic acids, preferably sulfuric acid or phosphoric acid, in a suitable solvent such as acetic acid or ethanol at elevated temperature. The acetals of formula XIII are prepared by alkylation

-14 ·· ···· secondary amines of formula V with acetals of formula XV (XV) using the conditions described above for processes a and b. Alternatively, acetals of formula XIII are prepared by alkylating acetals of formula XVI (XVI) with an alkylating agent of formula VI using the conditions described above for methods a and b. Acetals of formula XVI are prepared by reacting acetals of formula XV with primary amines of formula NH ² R ⁴ using standard conditions.

Polymer-bound acetals of formula XV are prepared by reacting aldehydes of formula GB-CH 2 CHO with commercially available 2,2-dimethyl-1,3-dioxolane-4-ylmethoxymethyl-polystyrene in a suitable solvent, such as toluene, using p-toluenesulfonic acid as catalyst in increased temperature. 4-Chlorobutanal, 5-chloropentanal and 6-chlorohexanal were prepared analogously to the method described by Normant et al., Tetrahedron 1994, 50 (40), 11665.

DETAILED DESCRIPTION OF THE INVENTION

Melting points were determined on a Biichi SMP-20 and are uncorrected. Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons Instruments. The MS-MS system was connected to an HP 1050 modular HPLC system. A volume of 20 to 50 μΙ of the sample (10 µg / ml) dissolved in 1% acetic acid in 1: 1 acetone itril / water was introduced via an autosampler at a flow rate of 30 μΙ / min into the electrospray source. Spectra were obtained in two standard sets of working conditions. Analytical LC-MS data was obtained using a PE Sciex API 15OEX instrument equipped with a lonSpray source and a Shimadzu LC-SA / SLC-10A LC system. LC conditions (50 x 4.6 mm YMC ODS-A with 5 pm) · · · · · · · · · · · · · · · · ·

-15 ·· ···· particle size) were a linear gradient of elution with water / acetonitrile / trifluoroacetic acid (90: 10: 0.05) to water / acetonitrile / trifluoroacetic acid (10: 90: 0.03) over 7 minutes at 2 ml / min. Purity was determined by integration in UV (254 nm). The retention times R t are expressed in minutes.

One set to obtain molecular weight (MH ⁺ ) information (21 eV) and the other set to induce fragmentation patterns (70 eV). Background subtracted. The relative ion intensities were obtained from the fragmentation pattern. When the intensity of the molecular ion (MH ⁺ ) is not visible, this ion was present only under the operating conditions of the first set. Preparative LC-MS separation was performed on the same instrument. LC conditions (50 x 20 mm YMC ODS-A with 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 minutes at

22.7 ml / min. Fraction collection was performed by split-flow MS detection.

¹ H 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. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) was used as solvent. . TMS was used as an internal comparison standard. Chemical shift values are expressed in ppm values. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet triplets, m = multiplet. NMR signals corresponding to acidic protons are generally omitted. The water content of the crystalline substance was determined by Karl-Fischer titration. Standard processing procedures relate to extraction with the indicated organic solvent from the respective aqueous solutions, drying of the combined organic extracts (anhydrous MgSO4 or Na2SO4), filtering and evaporation of the solvent under vacuum. Column chromatography employed Kieselgel 60, 230-400 mesh ASTM.

Example 1 (+) - 1- [3 - [[4- (1,4-Benzodioxan-5-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (1a)

·············································

-16 Mixtures of 5- (4-bromobutyl) -1,4-benzodioxane (1.5 g, 5.5 mmol), (+) - 1- [3- (methylamino) propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile (2.2 g, 5.5 mmol), potassium carbonate (3.0 g, 22 mmol) and methyl isobutyl ketone (150 mL) was 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 residual oil was purified by column chromatography (ethyl acetate / heptane / triethylamine 75: 20: 5) to give 2.0 g ( 73%) of the title compound as an oil: [α] ²² D + 8.63 ° (c 0.5, CH 3 OH). ¹ H NMR (CDCl 3) δ 1.25-1.35 (m, 1H), 1.40-1.60 (m, 5H), 2.05-2.30 (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, 1H); MS m / z 501 (MH < + >, 100), 262 (27), 149 (77), 109 (52).

The following substances were prepared analogously:

(+) - 1- [3 - [[3- (1,4-Benzodioxan-5-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, oxalate (1b): mp 114-16 ° C (ethyl acetate); [α] ²² D + 8.960 (c 1.0, CH 3 OH); ¹ H NMR (DMSO-d ₆ ) δ 1.35-1.45 (m, 1H), 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 (m, 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 < ^{+ &gt};, 100), 262 (33), 149 (52), 109 (55).

- [3 - [[2- (1,4-Benzodioxan-5-yl) ethyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, oxalate (1c): mp 118-20 ° C (ethyl acetate); ¹ H NMR DMSO-d6 δ 1.40-1.70 (m, 2H), 2.25 (t, 2H), 2.70 (s, 3H), 2.75-2.90 (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, 3H); 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-dihydroisobenzofuran-5-carbonitrile, oxalate (1d): mp 160-62 ° C (acetone / methanol); ¹ H NMR (DMSO-d 6) δ 1.40-1.70 (m, 2H), 2.25 (t, 2H), 2.60 (s, 3H), 2.90 (t, 2H), 4 , 00 (s, ·· ·! ·!

• ·· ·

-17 ·· · 99 · ··· · ···· · ·· ·· ·

9 · 999 · · · · · ·

2Η), 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, 1), 7.70-7.85 (m, 3H); MS m / z 459 (MH < ^{+ &gt};, 7), 109 (100).

Example 2

- (4-Fluorophenyl) -1- [3- [4- (2-methoxyphenyl) piperazinyl] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (2a)

A mixture of 1- (3-chloropropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2.5 g, 7.9 mmol), 1- (2-methoxyphenyl) piperazine (2.0 g, 10.4 mmol), potassium carbonate (3 g, 22 mmol) and methyl isobutyl ketone (200 mL) were boiled 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 residual oil was purified by column chromatography (ethyl acetate / heptane / triethylamine 75: 20: 5). the title compound was crystallized from diethyl ether 1.5 g (40%): mp 147-49 ° C; ¹ H NMR (DMSO-d 6) δ 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), 3.35 (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 < ^{+ &gt};, 100), 262 (14), 109 (19).

The following substances were prepared analogously:

- (4-Fluorophenyl) -1- [3 - [[2- (2-methoxyphenoxy) ethyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (2b): (oil) ¹ H NMR (CDCl 3) ) δ 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), 2.70-2.80 (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, 1 H), 7.55 (d, 1 H).

- (4-Fluorophenyl) -1- [3 - [[2- (3-methoxyphenoxy) ethyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (2c): (oil) ¹ H NMR (CDCl 3) ) δ 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), 2.70-2.75 (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, 1 H), 7.55 (d, 1 H).

-18 (S) -1- [3 - [[4- (1H-indol-3-yl) butyl] methylamino] propyl -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2d): LC / MS (m / z) 482 (MH +), Rt = 4.24, purity: 84%.

- [3 - [[4- (1H-Indol-3-yl) butyl] methylamino] propyl] -1-phenyl-1,3-dihydroisobenzofuran (2e): LC / MS (m / z) 439 (MH ⁺⁾ Rt = 4.33, purity: 77%.

(S) -1- [3 - [[3- (1H-Indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) _-1-L 3-dihydroisobenzofuran-5-carbonitrile (2f): LC / MS (m / z) 468 (MH ⁺ ), R t = 4.11, purity:> 99%.

1- [3 - [[3- (1H-Indol-3-yl) propyl] methylamino] propyl] -1-phenyl-1,3-dihydroisobenzofuran (2 g): LC / MS (m / z) 425 (MH +) ⁺ ), Rt = 4.15, purity:> 99%.

5- [3 - [[3- (1-Phenyl-1,3-dihydroisobenzofuran-1-yl) propyl] methylamino] propyl] -1,4-benzodioxane (2h): LC / MS (m / z) 444 ( MH +), Rt = 4.12, purity: 97%.

5- [3 - [[3- [1- (3-Chloro-phenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] methylamino] propyl] -

1,4-benzodioxane (2i): LC / MS (m / z) 478 (MH +), R t = 4.45, purity: 93%.

5- [3 - [(3- [1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl) methylamino] propyl] -

1,4-benzodioxane (2j): LC / MS (m / z) 462 (MH +), R t = 4.21, purity: 93%.

5- [3 - [[3- [1- (3-Trifluoromethyl-phenyl) -1,3-dihydroisobenzofuran-1-yl) propyl] methylamino] propyl] -1,4-benzodioxane (2k): LC / MS (m / m) z) 512 (MH +), Rt = 4.59, purity: 90%.

- [3 - [[3- (1,4-Benzodioxan-5-yl) propyl] methylamino] propyl] -1- (4-chlorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2I): LC / MS (m / z) 503 (MH +), R t = 4.59, purity:> 99%.

- (3- (4- (1H-Indol-yl) piperazinyl] propyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2m): LC / MS (m / z) 481 (MH +) ⁺ ), Rt = 5.61, purity: 97%.

- [3- [4- (1H-Indol-5-yl) piperazinyl) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2n): LC / MS (m / z) 481 (MH +), R t = 5.69, purity: 94%.

-19 ·· ····

1- [3- [4- (6-Chloro-1 H -indol-3-yl-) piperidinyl] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (2o): LC / MS (m / z) 514 (MH ⁺ ), R t = 6.33, purity: 96%.

Example 3

5- (3 - [[3 - [- 5-Fluoro-1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] methylamino] propyl] -1,4-benzodioxane oxalate ( 3)

A solution of 3- (1,4-benzodioxan-5-yl) propionic acid (0.8 g, 3.8 mmol), thionyl chloride (1 mL, 13.7 mmol) and one drop of N, N-dimethylformamide in dichloromethane (30 mL) was boiled under reflux for 2 hours. The volatile solvents were evaporated in vacuo and the remaining oil was dissolved in dichloromethane (30 mL). The resulting solution was added to a solution of [3 - [- 5-fluoro-1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] methylamine (3.0 g, 10 mmol) and triethylamine (10 mL). ) in dichloromethane (100 mL). After stirring for 16 hours, the volatile solvents were evaporated in vacuo and the residual oil was purified by column chromatography (ethyl acetate / heptane 75:25) to give 1.4 g of the crude amide which was used without further purification.

To a solution of the amide (1.4 g, 2.8 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydride (1.0 g, 2.6 mmol). After boiling the resulting mixture under reflux for 3 hours, the reaction mixture was cooled to 0 ° C and carefully treated with water (1 mL) and aqueous 4 M sodium hydroxide (1 mL). The resulting mixture was filtered and dried (Na ₂ SO ₄ ). Evaporation of the volatile solvents gave the title compound as an oil that precipitated as an oxalate in acetone 0.9 g (19%): mp 131-33 ° C; ¹ H NMR (DMSO-d ₆ ) δ 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), 45 7.60 (m, 3H); MS m / z, 480 (MH < ^{+ &gt};, 100), 225 (34), 109 (51).

Example 4

- [3 - [[2- (1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4a)

Into a suspension of acrylic ester Wang resin (CH2CHC (O) OR 'HOR' = ·· ···· ··

Wang resin) (1.0 mmol / g load) (300 mg, 0.30 mmol) (prepared from Wang resin (1.69 mmol / g capacity, 200-400 mesh, 1% divinylbenzene) by analogy to the procedure described for for the preparation of acrylic ester hydroxymethylpolystyrene from Brown et al., J. Am. Chem. Soc., 1997, 119, 3288-95) in N, N-dimethylformamide (1.5 ml) a solution of 2- (1H-indolyl-3) was added. -yl) ethylamine (96 mg, 0.60 mmol) in N, N-dimethylformamide (1.5 mL). After stirring the resulting suspension at room temperature for 16 hours, the resin was filtered off and then washed with 0.3 mol / l diisopropylethylamine in N, N-dimethylformamide (3 x 2.5 ml), methanol (2 x 2.5 ml) and dichloromethane (2 x 2.5 mL).

To a suspension of the resulting resin in acetonitrile (1.5 mL) was added a solution of 1- (3-chloropropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (9) (473 mg, 1.5 mmol). in acetonitrile (1.5 mL) and diisopropylethylamine (280 mL, 1.6 mmol). After heating the resulting mixture at 75 ° C with stirring for 16 hours, the resin was filtered off. The resin was then washed with acetonitrile (3 x 2.5 mL), methanol (3 x 2.5 mL) and dichloromethane (3 x 2.5 mL). The resin was suspended in N, N-dimethylformamide and diisopropylethylamine (280 mL, 1.6 mmol) and acetic anhydride (140 mL, 1.5 mmol) was added. After stirring the resulting mixture for 16 hours, the resin was filtered off and washed with N, N -dimethylformamide (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 -dimethylformamide (2 mL) and a solution of iodomethane (187 mL, 3.0 mmol) in N, N -dimethylformamide was added. After stirring the resulting mixture for 16 hours at room temperature, the resin was filtered off and washed with N, N -dimethylformamide (3 x 2.5 ml), methanol (3 x 2.5 ml) and dichloromethane (3 x 2.5 ml). ). N, N -dimethylformamide (3.0 mL) and diisopropylethylamine (165 mL, 0.94 mmol) were added to the resulting resin, and the mixture was stirred for 16 hours. The resin was filtered off and washed with methanol (2 x 2.0 mL). The digestion solution and washings were combined and the solvents were evaporated in vacuo. The remaining oil was purified by ion exchange chromatography using a 6 ml Varian SCX column (1225 - 6011). The column was preconditioned with 10% acetic acid in methanol (3 mL) and the crude product was loaded onto the column in a 2: 1 mixture of methanol and 1-methyl-2-pyrrolidinone (3 mL). Then the column was washed with methanol (18 ml) and acetonitrile (3 ml), the product was eluted from the column with a solution of 4 mol / l ammonia in methanol (4 ml), and

Subsequent evaporation of the solvent in vacuo gave 13.9 mg (10%) of the title compound as an oil: LC / MS (m / z) 454 (MH ⁺ ), R t = 6.13, purity: 98%.

The following substances were prepared analogously:

- (4-Fluorophenyl) -1- [3 - [[2- (3-methoxyphenyl) ethyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4b): LC / MS (m / z) 445 (MH ⁺ ), R t = 8.58, purity: 88%.

- (4-Fluorophenyl) -1- [3 - [[2- (3-methoxyphenyl) ethyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4c): ¹ H NMR (CDCl 3) δ 1.30 - 1.60 (m, 2H), 2.00 -

2.20 (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, Δ (t, 2H), 7.20 (t, 1H), 7.30 (6, 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-methoxyphenyl) ethyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile ( 4d): ¹ H NMR (CDCl 3) δ 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); 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%

- [3 - [[2- (2,5-Dimethoxyphenyl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4e): LC / MS (m / z) 475 (MH ⁺ ), R t = 8.68, purity: 94%.

- [3 - [[2- (2,5-Dimethoxyphenyl) ethyl] (prop-2-en-1-yl) amino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4f): LC / MS (m / z) 500 (MH ⁺ ), R t = 8.95, purity: 90%.

1- (4-Fluorophenyl) -1- [3 - [[2-phenoxyethyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4g): LC / MS (m / z) 431 (MH ⁺ ), R t = 8.58, purity: 95%.

·· ···· · ·

1- (3 - [[2- (1 H-Indolyl-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroizobenzofurán- 5-carbonitrile (4h): LC / MS (m / z) 480 (MH < ^{+ >} ), Rt = 8.87, purity: 93%.

- (4-Fluorophenyl) -1- [3 - [[2-phenoxyethyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4i): LC / MS (m / z) 457 (MH ⁺ ), R t = 6.40, purity:> 99%.

- (4-Fluorophenyl) -1- [3 - [[3- (2-methoxyphenyl) propyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4j): LC / MS (m / z) 459 (MH ⁺ ), R t = 6.43, purity:> 99%.

- (4-Fluorophenyl) -1- [3 - [[3- (2-methoxyphenyl) propyl] (prop-2-en-1-yl) amino] propyl] dihydroisobenzofuran-5-carbonitrile (4k): LC / MS (m / z) 485 (MH ⁺ ), R t = 6.77, purity:> 99%.

- (4-Fluorophenyl) -1- [3 - [(3- (3-methoxyphenyl) propyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4I) LC / MS (m / z) 485 (MH ⁺ ), R t = 6.63, purity:> 99%.

- (4-Fluorophenyl) -1- [3 - [[3- (2-methoxyphenoxy) propyl) methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4m): LC / MS (m / z) 475 (MH ⁺ ), R t = 6.20, purity:> 99%.

- (4-Fluorophenyl) -1- [3 - [[3- (2-methoxyphenoxy) propyl] (prop-2-en-1-yl) amino) propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4n) LC / MS (m / z) 501 (MH ⁺ ), R t = 6.50, purity:> 99%.

- (4-Fluorophenyl) -1- [3 - [[3- (3-methoxyphenoxy) propyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4o): LC / MS (m / z) 475 (MH ⁺ ), R t = 6.35, purity:> 99%.

1- (4-Fluorophenyl) -1- [3 - [[3- (3-methoxyphenoxy) propyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile (4p) LC / MS (m / z) 501 (MH ⁺ ), R t = 6.65, purity:> 99%.

1- [3 - ((2-Benzyloxyethyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4q): LC / MS (m / z) 445 (MH +), R t = 6.18, purity: 98%.

·· ····

1- [3 - [(2-Benzyloxyethyl) (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4r): LC / MS (m / z) 471 (MH ⁺ ), R t = 6.55, purity: 97%.

1- [3 - [[3- (1H-Indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) _-1-L 3-dihydroisobenzofuran-5-carbonitrile (4s): LC / MS ( m / z) 468 (MH ⁺ ), R t = 6.28, purity: 80%.

- (3 - ((3- (1H-indol-3-yl) propyl) (prop-2-en-1-yl) amino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbonitrile (4t): LC / MS (m / z) 494 (M-1 H, R t = 6.60, purity: 82%).

- (3 - ((3- (1H-Indol-3-yl) propyl) (prop-2-yn-1-yl) amino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile (4µ): LC / MS (m / z) 492 (MH ⁺ ), R t = 6.59, purity: 73%.

Example 5

5-Hydroxymethyl-1,4-benzodioxane (5)

To a suspension of lithium aluminum hydride (7.0 g, 0.18 mol) in dry diethyl ether (100 mL) was added a solution of ethyl 1,4-benzodioxane-5-carboxylate (35 g, 0.17 mol) in diethyl ether (100 mL). ). After boiling under reflux for 2 hours, the reaction mixture was cooled to 0 ° C and carefully treated with water (35 mL) and aqueous 4 mol / L sodium hydroxide solution (35 mL). The resulting mixture was filtered and dried (Na ₂ SO 4). Evaporation of the solvent gave 25 g (88%) of the title compound: mp 51-53 ° C; ¹ H NMR (CDCl ₃ ) δ 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-Benzodioxan-5-yl) acetic acid (6)

To a solution of 5-hydroxymethyl-1,4-benzodioxane (8.0 g, 48 mmol) in dichloromethane (200 mL) was added two drops of N, N -dimethylformamide and thionyl chloride (5.0 mL, 68 mmol) at room temperature. temperature. After the resulting solution was boiled under reflux for 1 hour and then cooled to room temperature, water (100 mL) was added. The phases were separated and the organic phase was dried (MgSO4) and the solvents were evaporated off.

-24vákua. 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 N, N-dimethylformamide (100 mL) at room temperature. After stirring for 16 hours at room temperature, ice was added and the resulting slurry was extracted with diethyl ether (2 x 250 mL). The combined organic phases were washed with saturated calcium chloride solution, dried (Na 2 SO 4) and the solvents were evaporated in vacuo. A mixture of the remaining oil (6.0 g, 34 mmol), ethanol (200 mL), sodium hydroxide (6.0 g) and water (6 mL) was boiled under reflux for 16 hours. After

evaporation of the solvent in vacuo water (200 mL) was added and the resulting slurry was extracted with diethyl ether (2 x 200 mL). The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ) and the solvents evaporated in vacuo to give 4.0 g (43%) of the title compound as an oil: ¹ H NMR (CDCl 3) δ 3 65 (s, 2H), 4.15 4.30 (m, 4H), 6.70-6.85 (m, 3H).

Example 7

5- (2-Bromomethyl) -1,4-benzodioxane (7a)

To a solution of 2- (1,4-benzodioxan-5-yl) acetic acid (6) (4.0 g, 21 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydride (1.0 g, 26 mmol). After boiling under reflux for 2 hours, the reaction mixture was cooled to 0 ° C and carefully treated with water (1 mL) and aqueous 4 M sodium hydroxide (1 mL). The resulting mixture was filtered and dried (Na ₂ SO ₄ ). Evaporation of the solvent gave the crude intermediate alcohol (3.9 g, 21 mmol) as an oil which was used without further purification. To a solution of the intermediate alcohol and tetra-bromomethane (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 reaction for an additional 15 min at 0 ° C, the solvents were evaporated in vacuo and the remaining oil was purified by column chromatography (ethyl acetate / heptane 66:34) to give 5.5 g (99%) of the title compound as an oil. ¹ H NMR (CDCl 3) δ 3.15 (t, 2H), 3.55 (t, 2H), 4.20-4.35 (m, 4H), 6.65-6.85 (m, 3H) ).

The following substances were prepared analogously:

5- (3-Bromopropyl) -1,4-benzodioxane (7b): (oil) ¹ H NMR (CDCl 3) δ 2.15 (qui, 2H), ·· ····

-252.75 (t, 2H), 3.40 (t, 2H), 4.20-4.30 (m, 4H), 6.65-6.75 (m, 3H).

5- (4-Bromobutyl) -1,4-benzodioxane (7c): (oil) ¹ H NMR (CDCl 3) δ 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-Bromoethoxy) -2-methoxybenzene (7d); (oil) ¹ H NMR (CDCl 3) δ 3.65 (t, 2H), 3.85 (s, 3H), 4.30 (t, 2H), 6.80-7.05 (m, 4H).

1- (2-Bromoethoxy) -3-methoxybenzene (7e): (oil) ¹ H NMR (CDCl 3) δ 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)

Pure 5- (4-bromomethyl) -1,4-benzodioxane (7c) (18.0 g, 74 mmol) was added to a mixture of diethyl malonate (12 g, 75 mmol), potassium tert-butoxide (8.4 g, 75 mmol). mmol), toluene (250 mL) and dimethylsulfoxide (50 mL) at room temperature. The resulting mixture was heated at 50 ^e C for 3 h, cooled to room temperature and water was added. After acidifying the slurry with concentrated hydrochloric acid, the phases were separated. The organic phase was dried (Na ₂ SO ₄ ) and the solvents were evaporated in vacuo. The remaining oil was dissolved in ethanol (200 mL) and aqueous 9 M sodium hydroxide. After boiling the resulting mixture under reflux for 15 minutes, the solution was stirred at room temperature for 1 hour. The solvents were evaporated and the remaining oil was diluted with water (200 mL) and extracted with diethyl ether (2 x 100 mL). The aqueous phase was acidified with 4 mol / L hydrochloric acid and extracted with ethyl acetate (2 x 200 mL). Drying of the combined organic phases and evaporation of the solvent in vacuo gave the intermediate dicarboxylic acid as an oil (5.0 g). The crude oil was diluted in pyridine (10 mL) and the resulting solution was heated to 115 ° C for 1 hour. After cooling to room temperature, water (50 mL) was added and the aqueous phase was acidified with 4 mol / L hydrochloric acid. The resulting slurry was extracted with diethyl ether (2 x 50 mL) and the combined organic phases were dried (Na ₂ SO ₄ ). Evaporation of the solvent in vacuo gave 3.8 g (23%) of the title compound as an oil.

·· ···· · ·

-26The following substance was prepared analogously:

3- (1,4-Benzodioxan-5-yl) propionic acid (8b): (oil) ¹ H NMR (CDCl 3) δ 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-dihydroisobenzofuran-5-carbonitrile (9).

To a mixture of 1- [3- (methylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (43 g, 138 mmol), potassium carbonate (30 g, 217 mmol) and ethanol (400 mL) was added ethyl bromoacetate (20 mL, 180 mmol) at room temperature and the resulting 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 added slowly to a mixture of ethyl chloroformate (50 mL, 523 mmol), potassium carbonate (36 g, 260) and toluene (300 mL) at 90 ° C. After boiling the resulting mixture under reflux for 1 hour and cooling to room temperature, the solvents were evaporated in vacuo. The remaining oil was purified by column chromatography (ethyl acetate / heptane 1: 3) to give 15 g (34%) of the title compound as an oil: ¹ H NMR (CDCl 3) δ 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); 60 (d, 1 H).

Example 10 [2- (2-Methoxyphenoxy) ethyl] methylamine (10a)

A solution of 1- (2-bromoethoxy) -2-methoxybenzene (7d) (7.7 g, 33 mmol) in a 33% solution of methylamine in ethanol was heated at 80 ° C in a sealed flask for 16 hours. After cooling to room temperature, the solvents were evaporated in vacuo. To the remaining oil was added 2 mol / L aqueous sodium hydroxide solution, and the resulting slurry was extracted with ethyl acetate (2 x 250 mL). The combined organic phases were dried (Na ₂ SO ₄ ) and the solvents evaporated in vacuo to give 5.9 g (98%) of the title compound as an oil: ¹ H NMR (CDCl 3) δ 1.85 (broad s 1 H, 2.50 (s, 3H), 3.00 (t

·· ···· · ·

-272 °), 3.85 (s, 3H), 4.10 (t, 2H), 6.85-6.95 (m, 4H).

The following material was prepared analogously: [2- (3-Methoxyphenoxy) ethyl] methylamine (10b): (oil) ¹ H NMR (CDCl 3) δ 1.85 (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,

Example 11

2- (4-Chlorobutyl) -dioxolan-4-ylmethoxymethyl-polystyrene (11a)

A round-bottomed flask was also charged with 2,2-dimethyl-dioxolan-4-ylmethoxymethyl-polystyrene (90 g, 72 mmol, commercially available as (±) -1- (2,3-isopropylidene) glycerol polystyrene from Calbiochem-Novabiochem, No. 01-64-0291). Toluene (900 mL) was added followed by p-toluenesulfonic acid (monohydrate) (5.0 g, 26 mmol), sodium sulfate (25 g), and readily available 5-chloropentanal (25.5 g, 211 mmol) and the mixture was stirred at room temperature. was heated under reflux for 12 hours. The reflux condenser was replaced with a Dean-Stark apparatus and the mixture was heated under reflux for an additional 3 hours. After cooling the reaction mixture to 60 ° C, the resin was filtered and washed with toluene (200 mL), tetrahydrofuran / pyridine (1: 1, 200 mL), tetrahydrofuran / water / pyridine (10: 10: 1, 200 mL), methanol ( 200 ml), water (200 ml), tetrahydrofuran (200 ml), dichloromethane (200 ml), methanol (3 x 200 ml) and dichloromethane (3 x 200 ml). The resin was dried under vacuum (55 ° C, 12 hours) to give the title compound 11a (97 g).

The following substances were prepared analogously:

2- (3-Chloropropyl) -dioxolan-4-ylmethoxymethyl-polystyrene (11b)

2- (5-Chloropentyl) -dioxolan-4-ylmethoxymethyl-polystyrene (11c)

Example 12

1- [3 - [[3- (1H-Indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (4s) ·· ··· · · · · · ·

2- (4-Chlorobutyl) -dioxolan-4-ylmethoxymethylpolystyrene (11a) (8.0 g, 6.1 mmol) was suspended in dry N, N -dimethylformamide (90 mL). Sodium iodide (3.38 g, 22.5 mmol) was added, followed by diisopropylethylamine (6.30 mL, 36 mmol) and 1- [3 (methylamino) propyl] -1- (4-fluorophenyl) -1,3 -dihydroisobenzofuran-5-carbonitrile (5.56 g, 18 mmol). The reaction mixture was heated at 80 ° C with 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), followed by methanol and tetrahydrofuran (each). 40 ml, 5 cycles). Finally, the resin was washed with tetrahydrofuran (4 x 40 mL) and dried under vacuum (55 ° C, 12 hours, 9.5 g).

An aliquot of this material (147 mg, 0.112 mmol) and phenylhydrazine hydrochloride (43 mg, 0.297 mmol) were mixed in the reaction flask. A 0.5 mol / L solution of anhydrous zinc chloride in acetic acid (1.5 mL) was added and the reaction flask 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 resulting resin was washed with dimethylsulfoxide (1.5 mL). Saturated aqueous sodium bicarbonate solution (1.5 mL) was added to the combined filtrates. The solution was loaded onto an inverted solid phase extraction column (C-18, 1 g, Varian 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 eluted with methanol (4.5 mL). The resulting solution was loaded onto an ion exchange column (SCX, 1 g, Varian Mega Bond Elut®, Chrompack Cat. No. 220776) preconditioned with 10% acetic acid in methanol (3 mL) and the column was washed with methanol (4 mL). and acetonitrile (4 mL), followed by elution with a 4 mol / L solution of ammonia in methanol (4.5 mL). Evaporation of the volatile solvents gave the title compound (4s) as a colorless oil (22 mg, 42%). LC / MS (m / z) 468 (MH ⁺ ), R t = 4.30, purity: 83%.

The following substances were prepared analogously:

- [3 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12a): LC / MS (m / z) 468 (MH ⁺ ), R t = 4.22, purity: 96%.

-291- [3 - [[2- (7-fluoro-1H-indol-3-yl) ethyl] aminomethyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbonitrile (12b): ¹ H NMR (CDCl 3) δ 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 ⁺ ), R t = 4.12, purity; 86%.

····

5-Fluoro-1- [3 - [[3- (5-methyl-1H-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran (12c): LC / MS (m / z) 475 (MH ⁺ ), R t = 4.57, purity: 92%.

5-Fluoro-1- [3 - [[3- (7-fluoro-1H-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran (12d) LC / MS (m / z) 479 (MH ⁺ ), R t = 4.47, purity: 94%.

- (3 - [[3- (5-Methyl-1H-indol-3-yl) propyl] methylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12e) LC / MS (m / z) 482 (M-1 '), R t = 4.54, purity: 80%.

1- [3- [Ethyl- [3- (1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12f); LC / MS (m / z) 482 (M-1 '), R t = 4.31, purity: 94%.

- [3- [Ethyl- [2- (5-methyl-1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile g): LC / MS (m / z) 482 (MH ⁺ ), R t = 4.38, purity: 89%.

- [3 - [[3- (7-Fluoro-1H-indol-3-yl) propyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12h): LC / MS (m / z) 486 (M-1 '), R t = 4.16, purity: 79%.

- [3 - [(3- (5-Fluoro-1H-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12i) ¹ H NMR (CDCl 3) δ 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); 7.47 (s, 1H); 7.55 (d, 1H); 1H); LC / MS (m / z) 486 (M-1 '), R t = 4.12, purity: 98%.

· Φ · • φ •

·· φ

-301- [3- [Ethyl- [2- (5-fluoro-1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 -carbonitrile (12j): ¹ H NMR (CDCl ₃ ) δ 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 (m, 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); 54 (d, 1 H), 8.01 (s, 1 H); LC / MS (m / z) 486 (MH +), R t = 4.24, purity: 95%.

- [3- [Ethyl 1- [2- (7-fluoro-1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 12k): ¹ H NMR (CDCl ₃ ) δ 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, 2 H),

5.12 (dd, IH), 5.16 (d, IH), 6.86-7.06 (m, 4H), 7.2-7.4 (m, 5H), 7.46 (d, 1H) 1H), 7.54 (d, IH); LC / MS (m / z) 486 (MH ⁺ ), R t = 4.26, purity: 91%.

- [3 - [[2- (5-chloro-1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (121): LC / MS (m / z) 488 (MH ⁺ ), R t = 4.30, purity: 85%.

- [3 - [[3- (5-chloro-1H-indol-3-yl) propyl] methylamino] propyl] -5-fluoro-1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12m) LC / MS (m / z) 495 (MH ⁺ ), R t = 4.64, purity: 94%.

- [3 - [[4- (5-methyl-1H-indol-3-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12n): LC / MS (m / z) 496 (MH ⁺ ), R t = 4.50, purity: 78%.

- [3- [Ethyl 1- [3- (5-methyl-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 12o): LC / MS (m / z) 496 (MH ⁺ ), R t = 4.50, purity: 92%.

- [3- [Ethyl- [3- (7-fluoro-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 12p): LC / MS (m / z) 500 (MH < ^{+ >} ), Rt = 4.39, purity: 91%.

- [3- [Ethyl- [3- (5-fluoro-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5- carbonitrile (12q): ¹ H NMR (CDCl ₃ ) δ 0.95 (t, 3H), 1.21-1.36 (m, 1H), 1.36-1.50 (m, 1H), 77 (tt, 2H), 2.10 (ddd, 1 H), 2.18 (ddd, 1 H), 2.34-2.50

···· φ

9 · m · 6 (m, 6 (), 2.65 (t, 2 Η), 5.12 (d, 1 Η), 5.15 (d, 1 Η), 6, 90-7.04 (m, 4Η), 7.20 (dd, 1H), 7.25 (dd, 1H), 7.30 (d, 1H), 7.36 (m, 2H), 7.45 (s, 1H); 7.52 (d, 1H); 8.12 (s, 1H); LC / MS (m / z) 500 (MH ⁺ ), R t = 4.35, purity: 94%.

- [3 - [[3- (5-chloro-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12r): LC / MS (m / z) 502 (MH ⁺ ), R t = 4.55, purity: 91%.

- [3 - ([2- (7-Chloro-1H-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12s): LC / MS (m / z) 502 (MH ⁺ ), R t = 4.41, purity: 80%.

1- [3 - [[2- (5-Chloro-1H-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12t): LC / MS (m / z) 502 (MH ⁺ ), R t = 4.44, purity: 95%.

1- (3 - ((2- (5,7-Difluoro-1H-indol-3-yl) ethyl] ethylamino] propyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12u LC / MS (m / z) 504 (MH +), R t = 4.35, purity: 92%.

1- [3 - [[4- (5-Fluoro-1H-indol-3-yl) butyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12v): LC / MS (m / z) 514 (MH ⁺ ), R t = 4.50, purity: 91%.

- [3 - [[4- (5-Chloro-1H-indol-3-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12w) ; LC / MS (m / z) 516 (MH ⁺ ), R t = 4.59, purity: 90%.

- [3 - [[3- (5-Chloro-1H-indol-3-yl) propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12x): LC MS (m / z) 516 (MH ⁺ ), R t = 4.56, purity: 97%.

1- [3 - [[3- (5,7-Difluoro-1/7-indol-3-yl) propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12y): LC / MS (m / z) 518 (MH ⁺ ), R t = 4.47, purity: 90%.

- [3 - [[2- (5-Bromo-1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12z): LC / MS (m / z) 532 (MH ⁺ ), R t = 4.46, purity: 87%.

··························································· I · ·· · ·· ··· ·

-321- [3 - [[3- (5-Bromo-1H-indol-3-yl) propyl] methylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12aa) LC / MS (m / z) 546 (MH ⁺ ), R t = 4.59, purity:

%.

- [3 - [[2- (5-Bromo-1H-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12ab): LC / MS (m / z) 546 (MH ⁺ ), R t = 4.50, purity: 90%.

1- [3 - [[4- (5-Bromo-1H-indol-3-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12ac): LC / MS (m / z) 560 (MH ⁺ ), R t = 4.61, purity: 90%.

- [3 - [(3- (5-Bromo-1H-indol-3-yl) propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12ad): LC / MS (m / z) 560 (M-1 '), R t = 4.62, purity: 92%.

- [3- [Ethyl 1- [2- (5-iodo-1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 12ae): LC / MS (m / z) 594 (MH ⁺ ), R t = 4.60, Purity: 82%.

1- [3- [Ethyl- [3- (5-iodo-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12af): LC / MS (m / z) 608 (MH ⁺ ), R t = 4.72, purity: 71%.

- [2 - [[4- (5-Chloro-1H-indol-3-yl) butyl] methylamino) ethyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12ag): LC / MS (m / z) 502 (M-1 '), R t = 4.50, purity: 90%.

1- [2 - [[4- (5-Bromo-1H-indol-3-yl) butyl] methylamino] ethyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12ah) LC / MS (m / z) 546 (MH ⁺ ), R t = 4.55, purity: 83%.

- [4 - [[2- (5,7-Difluoro-1H-indol-3-yl) ethyl] methylaminobutyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12ai) LC / MS (m / z) 504 (MH ⁺ ), R t = 4.36, purity: 87%.

1- [4 - [[2- (7-Chloro-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12a) LC / MS (m / z) 502 (M-1 '), R t = 4.42, purity: 70%.

· · ························ · · · -331- [4 - [[2- (5-Chloro-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12a) LC / MS (m / z) 502 (MH ⁺ ), R t = 4.45, purity: 91%.

- [4 - [[2- (5-Bromo-1H-indol-3-yl) ethyl) methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12a1): LC / MS (m / z) 546 (MH ⁺ ), R t = 4.48, purity: 90%.

- [4 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12am): LC / MS (m / z) 482 (MH ⁺ ), R t = 4.37, purity: 87%.

- [4 - [[2- (5-Iodo-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12an): LC / MS (m / z) 594 (MH ⁺ ), R t = 4.57, purity: 83%.

- [4 - [[2- (5- (2-methyl-2-propyl) -1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (12ao): LC / MS (m / z) 524 (MH < ^{+ >} ), Rt = 4.85, purity: 91%.

1- [4 - [[2- (5- (2-propyl) -1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12ap): LC / MS (m / z) 510 (MH ⁺ ), R t = 4.72, purity: 92%.

Example 13

- [3 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1 3dihydroisobenzofuran-5-carbonitrile (13a)

2- (3-Chloropropyl) -1,3-dioxolan-4-ylmethoxymethyl polystyrene (2.0 g, 1.6 mmol) was suspended in dry N, N-dimethylformamide (15 mL). Sodium iodide (0.67 g, 4.5 mmol) was 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 with stirring for 12 hours. After cooling to 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), followed by methanol and tetrahydrofuran (10 mL each, 5 cycles). Finally, the resin was washed with tetrahydrofuran (4 x 10 mL) and dried under vacuum (55 ° C, 12 hours). The resin was then suspended in dry N, N-dimethylformamide (20 mL). Sodium iodide (0.60 g, 4.0 mmol) was added, followed by diisopropylethylamine (0.48 mL,

2.7 mmol) and 1- (3-chloropropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (9) (0.79 g, 2.5 mmol). The reaction mixture was stirred for 12 hours at 80 ° C. After cooling to room temperature, the resin was filtered and washed with N, N-dimethylformamide (3x15 mL), methanol (3x15 mL), tetrahydrofuran (3x15 mL), followed by methanol and tetrahydrofuran (about 15 mL each, 5 cycles). Finally, the resin was washed with tetrahydrofuran (4 x 15 mL) and dried under vacuum (55 ° C, 12 hours, 2.1 g).

An aliquot of this material (120 mg, about 0.08 mmol) and 4-methylphenylhydrazine hydrochloride (about 40 mg, 0.20 mmol) were mixed in a reaction flask. A 0.5 mol / L solution of anhydrous zinc chloride in acetic acid (1.5 mL) was added and the reaction flask 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 dimethylsulfoxide (1.5 mL). Saturated aqueous sodium bicarbonate solution (1.5 mL) was added to the combined filtrates. The solution was loaded onto an inverted phase column (C-18.1 g, Vanan 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 eluted with methanol (4.5 mL). After evaporation of the volatile solvents, the crude product was purified by reverse phase preparative HPLC. The resulting solution was loaded onto an ion exchange column (SCX, 1 g, Varian Mega Bond Elut®, Chrompack Cat. No. 220776) preconditioned with 10% acetic acid in methanol (3 mL) and the column was washed with methanol (4 mL). and acetonitrile (4 mL), followed by elution with a 4 mol / L 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 pmol, 5%). LC / MS (m / z) 494 (MH ⁺ ), R t = 4.44, purity: 93%.

The following substances were prepared analogously:

1- [3 - [[2- (5-Fluoro-1H-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1, 3-Hydroisobenzofuran-5-carbonitrile (13b): LC / MS (m / z) 498 (MH ⁺ ), R t = 4.31, purity:

%.

······· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

1- [3 - [[2- (7-fluoro-1 H-indol-3-yl) ethyl) (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile (13c): LC / MS (m / z) 498 (M-1 '), Rt = 4.34, purity:

%.

- [3 - [[3- (5-Fluoro-1H-indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (13d): LC / MS (m / z) 512 (MH ⁺ ), R t = 4.48, purity: 96%.

- [3 - [[3- (7-Fluoro-1H-indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (13e): LC / MS (m / z) 512 (MH +), Rt = 4.49, purity: 78%.

- [3 - [[2- (5-Chloro-1H-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1, 3-Hydroisobenzofuran-5-carbonitrile (13f): LC / MS (m / z) 514 (MH ⁺ ), R t = 4.52, purity:

%.

- [3 - [[2- (5,7-Difluoro-1H-indol-3-yl) ethyl] propylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (13g) LC / MS (m / z) 518 (MH ⁺ ), R t = 4.47, purity:

%.

- [3 - [[2- [5- (2-Propyl) -1H-indol-3-yl] ethyl] (2-propyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile (13h): LC / MS (m / z) 524 (MH < ^{+ >} ), Rt = 4.78, purity:

%.

- [3 - [[3- (4-Fluoro-7-methyl-1H-indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile (13i): LC / MS (m / z) 526 (MH < ^{+ >} ), Rt =

4.65, purity: 83%.

1- [3 - [[2- (4-chloro-7-methyl-1 H-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl ) -1,3-dihydroisobenzofuran-5-carbonitrile (13j): LC / MS (m / z) 528 (MH ⁺ ), R t =

4.67, purity: 79%.

·· ····

1- [3 - [[3- (5-chloro-1H-indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (13k): LC / MS (m / z) 528 (MH < ^{+ >} ), Rt = 4.63, purity: 78%.

- [3 - [[2- (5-Pyrolo [3,2-h] -1H-quinolin-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1 - ( 4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (131): LC / MS (m / z) 531 (MH ⁺ ), R t = 3.43, purity: 91%.

1- [3 - [[3- (7-Fluoro-1H-indol-3-yl) propyl] (2-furylmethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 13m): LC / MS (m / z) 552 (MH ⁺ ), R t = 4.58, purity: 82%.

- [3 - [[4- (7-Carboxy-1H-indol-3-yl) butyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile (13n); LC / MS (m / z) 552 (MH ⁺ )> R t = 4.17, purity: 69%.

1- [3 - [[2- [5-Bromo-1H-indol-3-yl] ethyl] -propylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (13o) LC / MS (m / z) 560 (MH ⁺ ), R t = 4.62, purity: 96%.

- [3 - [[3- (1H-indol-3-yl) propyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 13p): LC / MS (m / z) 574 (MH ⁺ ), R t = 4.78, purity: 93%.

- [3 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] (2-phenoxyethyl) amino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (13q): LC / MS (m / z) 574 (MH ⁺ ), R t = 4.82, purity: 93%.

- (3 - [[2- (5-Fluoro-1H-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 13r): LC / MS (m / z) 578 (M-1 '), R t = 4.71, purity: 95%.

- [3 - [[3- (1H-Pyrolo [3,2-h] quinolin-3-yl) propyl] (2-furylmethyl) amino] propyl] -1- (4-fluoro) ·· ··· ·

-37 Phenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (13s): LC / MS (m / z) 585 (MH ⁺ ), R t = 3.60, purity: 90%.

1- [3 - [[3- (5-Methyl-1 H-indol-3-yl) propyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (13t): LC / MS (m / z) 588 (MH ⁺ ), R t = 4.96, purity: 82%.

- [3 - [[3- (5-Fluoro-1H-indol-3-yl) propyl] (2-phenoxyethyl) amino) propyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (13u): LC / MS (m / z) 592 (MH ⁺ ), R t = 4.82, purity: 90%.

- [3 - [[2- (5,7-Difluoro-1H-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (13v): LC / MS (m / z) 596 (MH +), Rt = 4.84, purity: 92%.

- [3 - [[4- (1H-Pyrolo [3,2-h] -quinolin-3-yl) butyl] (2-furylmethyl) amino] propyl] -1- (4-fluorophenyl) -1,3 -dihydroisobenzofuran-5-carbonitrile (13w): LC / MS (m / z) 599 (MH ⁺ ), R t = 3.71, purity: 83%.

- [3 - [(2-Phenoxyethyl) [2- [5- (2-propyl) -1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -

1,3-dihydroisobenzofuran-5-carbonitrile (13x): LC / MS (m / z) 602 (M-1 '), Rt = 5.24, purity: 78%.

1- [3 - [[2- (5-Bromo-1H-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 13y): LC / MS (m / z) 638 (MH ⁺ ), R t = 4.98, purity: 91%.

Example 14

1- (3-Iodopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (14a)

1- (3-Chloropropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile solution / suspension (20 g, 35 mmol, 80% pure) and sodium iodide (285 g, 1.9 mol) in su ·· ····

-38CH acetone (200 mL) was heated under reflux for 24 hours. The mixture was evaporated and partitioned between ether and water. The ether layer was separated and washed sequentially with water and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to give 1- (3-iodopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (25.8 g, 99%, 80% purity) as a thick oil. ¹ H NMR (CDCl ₃ ) δ 1.6-1.9 (m, 2H), 2.21 (ddd, 1H), 2.31 (ddd, 1H), 3.16 (td, 2H), 5, 12 (dt, 1 H), 5.21 (dt, 1 H), 7.02 (t, 2 H), 7.41 (d, 2 H), 7.43 (d, 1 H), 7.51 (s, 1 H) ), 7.62 (dq, 1 H)

The following compounds were prepared analogously: 1- (2-iodoethyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (14b): yellow oil, ¹ H NMR (CDCl ₃ ) δ 2.4 - 2.9 (m, 2H), 3.38 (dt, 1H), 3.46 (dt, 1H), 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).

1- (4-Iodobutyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (14c): yellow oil, ¹ H NMR (CDCl 3) δ 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, IH).

Example 15

- (3- (Ethylamino) propyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (15a)

To a stirred solution of 1- (3-iodopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (12.9 g, 30 mmol, 8% purity) in ethanol (150 mL) was added a solution ethylamine (20.3 g, 450 mmol) in THF (50 mL) in portions, and the mixture was stirred overnight. The solution was evaporated and dissolved / suspended in water. The pH was adjusted to 12 using 2M aqueous sodium hydroxide solution and the mixture was extracted with ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. This oil was purified by silica gel chromatography using 50% ethyl acetate / heptane as eluent followed by 10% triethylamine / 40% ethyl acetate / heptane followed by 20% triethylamine / ethyl acetate to give the title compound of this paragraph (5,52 g, 57%) as ·· ······

-39 Pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 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, 1H), 7.58 (ddt, 1H).

The following substances were prepared analogously:

- (2- (Methylamino) ethyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (15b): yellow oil; ¹ H NMR (CDCl 3) δ 2.38 (s, 3H), 2.33-2.72 (m, 4H), 5.13 (d, 1H), 5.20 (d, 1H), 7.01 (t, 2H), 7.37-7.47 (m, 3H), 7.50 (s, 1H), 7.59 (d, 1H).

1- (4- (Methylamino) butyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (15c): yellow oil; ¹ H NMR (CDCl ₃ ) δ 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 (m, 3H), 7.49 (s, 1 H), 7.59 (d, 1 H).

Pharmacological testing

The affinity of the compound of the invention for 5-HT1A receptors was determined by measuring the inhibition of radioactive ligand binding to 5-HT1A receptors as described in the following assay:

Inhibition of ³ H-5-CT binding to human 5-HT 1A receptors

This method determines the in vitro inhibition of drug binding of 5-HT _1A agonist ³ H-5-carboxamidotryptamine ( ³ H-5-CT) to cloned human 5-HT _1A receptors stably expressed in transfected HeLa cells (HA7) (Fargin, A. et al., J Biol. Chem., 1989, 264, 14848). The assay is performed as a modification of the method described by Harrington, MA et al., J. Pharmacol. Exp. Ther, 1994, 268, 1098, Human 5-HT 1A receptors (40 µg cell homogenate) were incubated for 15 minutes at 37 ° C in 50 mM Tris buffer at pH 7.7 in the presence of ³ H-5-CT. Non-specific binding was determined by incorporation of 10 pmol / L metergoline. The reaction was terminated by rapid filtration through Unifilter OF / B filters on a Tomtec Cell Harvester. Filters were measured on a Packard Top Counter. The results obtained are shown in Table 1 below.

The compounds of the present invention have also been tested for their effect on B-1-B-1-B-1 · • · ··

B tB • B · B

-40 serotonin absorption in the following assay:

Inhibition of ³ H-5-HT re-uptake into rat brain synaptosomes

Using this method, the ability of a drug to inhibit the accumulation of ³ H-5-HT in whole rat brain synaptosomes is determined in vitro. The assay was performed as described in Hyttel, J., Psychopharmacology 1978, 60, 13. The results obtained are shown in Table 1:

Table 1

Substance no. Inhibition of ³ H-5-CT binding (50 nmol / L)% inhibition at 100 nmol / L Inhibition of serotonin reabsorption (IC 50 nmol / L)% inhibition at 100 nmol / L 1 39 60 1b 12 13 1c 53 85 2 1.0 340 2b 6.4 40 2e 38 15 2f 8.6 14 2 g 40 20 2J 41 9.7 2 m 4.7 untested 2n 15 untested 2o 12 31 4a 23 - 4b 63 59% inh. at 100 nmol / l 4c 11 4% inh. at 100 nmol / l 4d 4.5 7% inh. at 100 nmol / l 4e 17 160

·· ·

-41 ·· 9

99 · 9 · 9 · 9 · 9 · 9 · 9 · 9

999 • · • · ··

4f 1.6 4% inh. at 100 nmol / l 4 g 18 28% inh. at 100 nmol / l 4h 3.2 69 4i 1.9 26% inh. at 100 nmol / l 4J 6.1 78 4k 0.42 100 4I 76% inh. at 100 nmol / l 27% inh. at 100 nmol / l 4 m 65% inh. at 100 nmol / l 74% inh. at 100 nmol / l 4n 14 39% inh. at 100 nmol / l 4o 26 73 4p 19 6% inh. at 100 nmol / l 4q 16 60% inh. at 100 nmol / l 4r 11 19% inh. at 100 nmol / l 4s 30 35 4 t 69% inh. at 100 nmol / l 73% inh. at 100 nmol / l 4u 58% inh. at 100 nmol / l 44% inh. at 100 nmol / l 12b 43 10 12c 19 17 12d 31 12 12f 4.7 13 12i 27 20 12j 7.9 14 12k 3.6 8.4 12o 62 49% inh. at 100 nmol / l 12p 19 11 12q 12 6.3 12 years 16 47% inh. at 100 nmol / l 12s 7.7 18 12u 9.0 22 12v 39 12

12x 14 50% inh. at 100 nmol / l 12a 16 37% inh. at 100 nmol / l 12ab 20 50% inh. at 100 nmol / l 12ad 21 35% inh. at 100 nmol / l 12ae 11 49% inh. at 100 nmol / l 12AF 31 38% inh. at 100 nmol / l 13b 7.4 44 13c 9.6 12 13d 15 21 13e 22 27 13f 31 16% inh. at 100 nmol / l 13 grams 18 49% inh. at 100 nmol / l 13j 16 61% inh. at 100 nmol / l 13k 19 untested 13p 23 untested 13q 12 untested 13r 8.9 untested 13 tons 23 untested 13U 22 untested 13v 23 untested 13x 26 untested pindolol 100 paroxetine * 0.29

Table 1 * Reference substances

Furthermore, 5HT IA antagonistic activity of some of the compounds of the invention was determined in vitro at cloned _5-HT-A receptor and stably-expressed in transfected HeLa cells (HA7). In this assay, 5-HT _1A antagonist activity was determined by measuring the ability of the agent to antagonize 5-HT-induced inhibition of forskolin-induced cAMP accumulation. The test was performed as

• 9 • 9 • 9 • 9 • 9 • 9

43 modification of the method described in Pauwels, P.S. and with pol., Biochem. Pharmacol. 1993, 45,375.

As can be seen from the above, the compounds of the invention exhibit affinity for the 5-HT 1A receptor. In addition, many of the compounds of the invention have valuable activity as serotonin reabsorption inhibitors.

Accordingly, these agents are considered useful for the treatment of psychiatric and neurological disorders, as mentioned above.

Pharmaceutical preparations

The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example: Tablets may be prepared by mixing the active ingredient with conventional adjuvants and / or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvants or additives normally used for such purposes, such as coloring agents, flavors, preservatives, etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling into suitable ampoules or vials. Any suitable additives conventionally used in the art, such as tonicity agents, preservatives, antioxidants, etc. may be added.

The pharmaceutical compositions of the invention or compositions produced in accordance with the invention may be administered by any suitable method, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For the preparation of 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.

The compounds of the invention are suitably administered in unit dosage form containing these in an amount of about 0.01 to 1000 mg. Total Daily ····················

The dosage is usually in the range of about 0.05 to 500 mg, and most preferably about 0.1 to 50 mg of the active ingredient of the invention.

································

-45- 7 / 'Π-ζ-Ιο & Ι

Claims (34)

Isobenzofuran derivatives of the general formula I wherein R ¹ is hydrogen, halogen, trifluoromethyl, trifluoromethylsulfonyloxy, C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 1-6 -alkoxy, hydroxyl, formyl, acyl, amino, C 1-6 -alkyl; ₆ alkylamino, C ₂ -i2-di-alkylamino, Ci-6-alkoxycarbonylamino, aminocarbonylamino, C ₆ -alkylaminokarbonylaminoskupina, C2, 2-dialkylaminocarbonylamino, nitro, cyano, COOH, or COO-Ci-6-alkyl; R ² and R ³ are each independently selected from hydrogen, trifluoromethyl, C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl and C 1-6 -alkoxy; n is 1, 2, 3, 4 or 5; m is 0 or 1; A is selected from the following groups: R ⁴ '- (D) - (Z) - —nQ ^ N— - ^_N Cv (1) (2) (3) (4) where Z is O or S; s is 0 or 1; w is 0 or 1; R ⁴ is hydrogen, C ^ alkyl, _C2 -6 alkenyl, _C2 -6 alkynyl, C. _6- alkyl-Aryl, or C 1-6 alkyl; _6- alkyl-OAryl, ·· ···· -46D is a spacer group selected from branched or straight chain C 6alkylénu, C _2, 6-alkenylene and C 2-6 alkynylene; B is a group selected from Formula II, III and IV wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from R ¹ substituents; or R ⁸ and R ⁹ together form a fused 5- or 6-membered ring optionally containing additional heteroatoms; and the resulting heterocycle is optionally substituted with substituents selected from R ¹ substituents; or two of R ⁵ , R ⁶ and R ⁷ are bonded together to form a -O- (CH ₂ ) _p -O- bridge wherein 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, 1-indolyl, 2-indolyl, 3-indolyl, indole- 2-one-1-yl, indol-2-one-3-yl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each of which is optionally substituted with halogen, C _1-6 alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, hydroxyl, C _1-6 -alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, C 3-8 cycloalkyl, C 3-8 -cycloalkyl-C 1-6 alkyl, nitro, C 1-6 amino, C 1-6 amino, ₂ .i ₂ -dialkylamino, acylamino or alkylenedioxy; their enantiomers and their pharmaceutically acceptable acid addition salts. The isobenzofuran derivatives according to claim 1, wherein A is a group of formula 1. The isobenzofuran derivatives according to claim 1, wherein A is a group of formula 2. The isobenzofuran derivatives of claim 1, wherein A is a group of Formula 3. ························································ · · · · · · · · · · · · · · The isobenzofuran derivatives of claim 1, wherein A is a group of Formula 4. The isobenzofuran derivatives of claim 2, wherein R ⁴ is methyl, ethyl, propyl, 2-Propen-1-yl, 2-furylmethyl, 2-phenoxyethyl. The isobenzofuran derivatives according to claims 2 and 6, wherein q = 0. The isobenzofuran derivatives of claims 2 and 6, wherein q = 1 and Z is 0. The isobenzofuran derivatives according to any one of claims 1 to 8, wherein B is a group of formula II. Isobenzofuran derivatives according to any one of claims 1 to 8, wherein B is a group of formula III. The isobenzofuran derivatives according to any one of claims 1 to 8, wherein B is a group of formula IV. The isobenzofuran derivatives according to claim 9, wherein at least one of R ⁵ , R ⁶ and R ⁷ is methoxy. The isobenzofuran derivatives according to claim 9, wherein the group of formula II is a benzodioxane group or a 1,2-methylenedioxybenzene group. The isobenzofuran derivatives of claim 10, wherein the group of formula III is 3-indolyl. The isobenzofuran derivatives of claim 14, wherein the 3-indolyl is substituted at the 5-position with methyl, fluorine, chlorine, bromine, iodine, tert-butyl or isopropyl, or at the 7-position with fluorine, chlorine or carboxyl; or disubstituted with 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro-7-methyl or two substituents together form a pyridyl ring fused to 3-indolyl. ·· · ·· ···· The isobenzofuran derivatives of claim 11, wherein the group of formula IV is A 4-indolyl or 5-indolyl group. The isobenzofuran derivatives of any one of claims 1 to 16, wherein Ar is phenyl or phenyl substituted with halogen or CF 3. The isobenzofuran derivatives of claim 17, wherein Ar is phenyl, which may be substituted with Cl or F at the 4-position or Cl or CF 3 at the 3-position. The isobenzofuran derivatives according to any one of claims 1 to 18, wherein R ¹ is H, CN or F at the 5-position of the isobenzofuran group. The isobenzofuran derivatives according to any one of claims 1 to 19, wherein R ² and R ³ are selected from hydrogen or methyl. Isobenzofuran derivatives according to any one of claims 1 to 20, wherein n = 2, 3 or 4. The isobenzofuran derivatives of claim 21, wherein n = 3. Isobenzofuran derivatives according to any one of claims 1 to 22, wherein m = 0. Isobenzofuran derivatives according to any one of claims 1, 18, 19, 20, 21, 22 and 23, wherein R ² and R ³ are both hydrogen; R ¹ is H, CN or F at the 5-position of the isobenzofuran group; and Ar is phenyl, which may be substituted with F or Cl at the 4-position or with Cl or CF 3 at the 3-position. The isobenzofuran derivatives of any one of claims 1 to 24, wherein A is a group of Formula 1; q = 0; R ⁴ is methyl; D is propylene; m = 0; and B is a 1,4-benzodioxane group of formula II attached at the 5-position. ·· ···· Isobenzofuran derivatives according to any one of claims 1 to 24, wherein A is a group of 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. The isobenzofuran derivatives of any one of claims 1 to 24, wherein A is a group of Formula 1; q is 0; R ⁴ is methyl, ethyl, propyl, 2-propen-1-yl, 2-furylmethyl or 2-phenoxyethyl; D is ethylene or propylene; m = 0; and B is a 3-indolyl group of formula III. The isobenzofuran derivatives of claim 27, wherein the 3-indolyl group is substituted with methyl, fluoro, chloro, bromo, iodo, tert-butyl or isopropyl at the 5-position; or by fluorine, chlorine or carboxyl at the 7-position; or 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro-7-methyl; or two substituents together form a pyridyl ring fused to a 3-indolyl group. Isobenzofuran derivatives according to any one of claims 1 to 24, wherein A is a group of formula 2 or 3; n = 3; m = 0; and B is a 4- or 5-indolyl group of formula IV wherein R ¹⁰ is hydrogen; R ¹ is CN at the 5-position of isobenzofuran and Ar is 4-fluorophenyl. The isobenzofuran derivatives of claim 1, selected from the group consisting of: (-) - 1- [3 - [[4- (1,4-Benzodioxan-5-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1 - [3 - [[3- (1 _L 4-benzodioxan-5-yl) propyl] methylamino] propyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile oxalate, 1- [3 - [[2- (1,4-Benzodioxan-5-yl) ethyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, oxalate, 1- [3 - [[1,4-Benzodioxan-5-ylmethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, oxalate, 1- (4-Fluorophenyl) -1- [3- [4- (2-methoxyphenyl) piperazinyl] propyl] -1,3-dihydroisobenzofuran- 5-carbonitrile, e ··· · e ·········· -501- (4-Fluorophenyl) -1- [3-methyl - [[2- (2-methoxyphenoxy) ethyl] amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3-methyl - [[2- (3-methoxyphenoxy) ethyl] amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, (S) -1- [ 3 - [[4- (1 H-Indol-3-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[4- (1H-indol-3-yl) butyl] methylamino] propyl] -1-phenyl-1,3-dihydroisobenzofuran, (S) -1- [3 - [[3] - (1H-Indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[3- (1H-Indol-3-yl) propyl] methylamino] propyl] -1-phenyl-1,3-dihydroisobenzofuran, 5- [3 - [[3- (1-Phenyl-1,3-dihydroisobenzofuran-1-yl) propyl] methylamino] propyl] -1,4benzodioxán, 5- [3 - [[3- [1- (3-Chloro-phenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] methylamino] propyl] - 1,4-benzodioxan, 5- [3 - [(3- [1- (4-Fluorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl) methylamino] propyl] - 1,4-benzodioxan, 5- [3 - [[3- [1- (3-trifluoromethylphenyl) -1,3-dihydroisobenzofuran-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- (1H-Indol-4-yl) piperazinyl] propyl] -1- (4-fluorophenyl) -1,3-dihydroizobenzofurán5-carbonitrile, 1- [3- [4- (1H-indol-5-yl) piperazinyl] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [4- (1H-Indol-3-yl) piperazinyl) propyl] -1- (4-fluorophenyl) -1,3-dihydroizobenzofurán5-carbonitrile, 5- (3 - [[3 - [- 5-Fluoro-1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-1-yl] propyl] methylamino] propyl] -1,4-benzodioxane, 1- [3 - [[2- (1 H-Indolyl-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [[2- (3-methoxyphenyl) ethyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, · · • ·· ···· • a • • · • • e · • • · · • a • · • · · • • • • • MM • · · · • · • • and • • • · · • • • · · • ·· · · · · · · 1- (4-Fluorophenyl) -1- [3 - [[2- (3-methoxyphenyl) ethyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5- carbonitrile 1- (4-Fluorophenyl) -1- [3 - [[2- (2-methoxyphenyl) ethyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (2,5-Dimethoxyphenyl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (2,5-Dimethoxyphenyl) ethyl] (prop-2-en-1-yl) amino] propyl I-1- (4-fluorophenyl) -1,3 dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [[2-phenoxyethyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (3 - [[2- (1H-Indolyl-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran 5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [[2-phenoxyethyl] (prop-2-en-1-yl) amino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 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-1-yl) amino] propyl] dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [(3- (3-methoxyphenyl) propyl] (prop-2-en-1-yl) amino] propyl] -1,3dihydroizobenzofurán-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [[3- (2-methoxyphenoxy) propyl) methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [[3- (2-methoxyphenoxy) propyl] (prop-2-en-1-yl) amino) propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [[3- (3-methoxyphenoxy) propyl] methylamino] propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- (4-Fluorophenyl) -1- [3 - [[3- (3-methoxyphenoxy) propyl] (prop-2-en-1-yl) amino) propyl] -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - ((2-Benzyloxyethyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [(2-Benzyloxyethyl) (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile. ·· ···· · · -521- [3 - [(3- (1/7-Indolyl-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3dihydroizobenzofurán 5-carbonitrile, 1- [3 - [(3- (1 H-Indolyl-3-yl) propyl] (2-propynyl) amino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[3- (1 H-Indolyl-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3dihydroizobenzofurán-5-carbonitrile, 1- [3 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 carbonitrile, 1- [3 - [[2- (7-Fluoro-1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile . 5-Fluoro-1- [3 - [[3- (5-methyl-1H-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran, 5-Fluoro-1- [3 - [[3- (7-fluoro-1H-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran, 1- (3 - [[3- (5-Methyl-1H-indol-3-yl) propyl] methylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl- [3- (1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [ethyl [2- (5-methyl-1 H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3dihydroizobenzofurán-5-carbonitrile, 1- [3 - [[3- (7-Fluoro-1H-indol-3-yl) propyl) methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [(3- (5-Fluoro-1H-indol-3-yl) propyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl- [2- (5-fluoro-1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl- [2- (7-fluoro-1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5-Chloro-1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[3- (5-Chloro-1H-indol-3-yl) propyl] methylamino] propyl] -5-fluoro-1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, ·· ···· · · 1- [3 - [[4- (5-Methyl-1H-indol-3-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl- [3- (5-methyl-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl 1- [3- (7-fluoro-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5- carbonitrile 1- [3- [Ethyl 1- [3- (5-fluoro-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 carbonitrile, 1- [3 - [[3- (5-chloro-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - ([2- (7-Chloro-1H-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5- carbonitrile 1- [3 - [[2- (5-Chloro-1H-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3- dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5,7-Difluoro-1H-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[4- (5-Fluoro-1 H -indol-3-yl) butyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[4- (5-Chloro-1H-indol-3-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile . 1- [3 - [[3- (5-chloro-1H-indol-3-yl) propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[3- (5,7-Difluoro-1H-indol-3-yl) propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5-Bromo-1H-indol-3-yl) ethyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[3- (5-Bromo-1H-indol-3-yl) propyl] methylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5-Bromo-1H-indol-3-yl) ethyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[4- (5-Bromo-1 H -indol-3-yl) butyl] methylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, ·· ···· 1- [3 - [(3- (5-Bromo-1H-indol-3-yl) propyl] ethylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl- [2- (5-iodo-1H-indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3- [Ethyl 1- [3- (5-iodo-1H-indol-3-yl) propyl] amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5- carbonitrile 1- [2 - [[4- (5-Chloro-1H-indol-3-yl) butyl] methylamino) ethyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [2 - [[4- (5-Bromo-1 H -indol-3-yl) butyl] methylamino] ethyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile, 1- [4 - [[2- (5,7-Difluoro-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile, 1- [4 - [[2- (7-chloro-1 H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4 - [[2- (5-Chloro-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4 - [[2- (5-Bromo-1H-indol-3-yl) ethyl) methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 carbonitrile, 1- [4 - [[2- (5-Iodo-1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4 - [[2-tert-Butyl] -1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [4 - [[2- (5-i-Propyl) -1H-indol-3-yl) ethyl] methylamino] butyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile . 1- [3 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4- fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5-Fluoro-1H-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) ) -1,3dihydroizobenzofurán-5-carbonitrile, 1- [3 - [[2- (7-Fluoro-1H-indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, ·· ···· 9 -551- [3 - [[3- (5-Fluoro-1 H -indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4 fluorophenyl) IS-dihydroisobenzofuran-S-carbonitrile, 1- [3 - [[3- (7-Fluoro-1H-indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1 - (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5-Chloro-1 H -indol-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) ) -1,3dihydroizobenzofurán-5-carbonitrile, 1- [3 - [[2- (5,7-Difluoro-1H-indol-3-yl) ethyl] propylamino] propyl] -1- (4-fluorophenyl) -1,3- dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- [5- (2-Propyl) -1H-indol-3-yl] ethyl] (2-propyl) amino] propyl) -1- (4-fluorophenyl) -1 , 3dihydroizobenzofurán-5-carbonitrile, 1- [3 - [[3- (4-Fluoro-7-methyl-1H-indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1 - ( 4-Fluorophenyl) -1,3-diisobenzofuran-5-carbonitrile, 1- [3 - [[2- (4-Chloro-7-methyl-1H-indol-3-yl) ethyl] (prop-2- en-1-yl) amino] propyl] -1- (4-fluorophenyl-IS-dihydroisobenzofuran-S-carbonitrile, 1- [3 - [[3- (5-chloro-1H-indol-3-yl) propyl] (prop-2-en-1-yl) amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5-pyrrolo [3,2-h] -1 / 7-quinolin-3-yl) ethyl] (prop-2-en-1-yl) amino] propyl] -1 - (4-fluorophenyl-IS-dihydroisobenzofuran-S-carbonitrile, 1- [3 - [[3- (7-Fluoro-1H-indol-3-yl) propyl] (2-furylmethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5- carbonitrile 1- [3 - [[4- (7-carboxy-1H-indol-3-yl) butyl] (prop-2-en-1-yl) amino) propyl] -1- (4-fluorophenyl-IS-dihydroisobenzofuran-S carbonitrile, 1- [3 - [[2- [5-Bromo-1H-indol-3-yl] ethyl] propylamino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran 5-carbonitrile, 1- [3 - [[3- (1H-Indol-3-yl) propyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-ca rbonitri I, 1- [3 - [[2- (5-Methyl-1H-indol-3-yl) ethyl] (2-phenoxyethyl) amino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile, 1- (3 - [[2- (5-Fluoro-1H-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1,3dihydroizobenzofurán-5-carbonitrile, 1- [3 - [[3- (5-Pyrrolo [3,2-h] -1 H -quinolin-3-yl) propyl] (2-furylmethyl) amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, ·· · ··· 1- [3 - [[3- (5-Methyl-1H-indol-3-yl) propyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[3- (5-Fluoro-1H-indol-3-yl) propyl] (2-phenoxyethyl) amino) propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[2- (5,7-Difluoro-1/7-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile, 1- [3 - [[4- (5-Pyrolo [3,2-h] -1H-quinolin-3-yl) butyl] (2-furylmethyl) amino] propyl] -1- (4-fluorophenyl) -1,3 dihydroisobenzofuran-5-carbonitrile, 1- [3 - [(2-Phenoxyethyl) [2- [5- (2-propyl) -1 H -indol-3-yl) ethyl] amino] propyl] -1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran-5-carbonitrile; or 1- [3 - [[2- (5-Bromo-1H-indol-3-yl) ethyl] (2-phenoxyethyl) amino] propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 -carbonitrile, or acid addition salts thereof. 31. A pharmaceutical composition comprising the isobenzofuran derivative according to claims 1 to 30 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. Isobenzofuran derivatives according to claims 1 to 30, or pharmaceutically acceptable acid addition salts thereof, for use in the treatment of disorders or diseases of animals, including humans, sensitive to the action of 5-HT 1A receptors. The isobenzofuran derivatives of claim 32, wherein the disorder or disease is depression, psychosis, anxiety disorders, panic disorder, obsessive compulsive disorder, impulsive control disorder, alcohol addiction, aggression, ischemia, senile dementia, cardiovascular disorder or social phobia. Use of the isobenzofuran derivatives according to claims 1 to 30 or pharmaceutically acceptable acid addition salts thereof for the manufacture of a medicament for the treatment of disorders or diseases susceptible to the action of 5-HT 1A receptors. e · -5735. Use of isobenzofuran derivatives according to claim 32, wherein the medicament is for the treatment of depression, psychosis, anxiety disorders, panic disorder, obsessive-compulsive disorder , impulsive control disorders, alcohol addiction, aggression, ischemia, senile dementia, cardiovascular disorders and social phobia.