WO2008146064A1

WO2008146064A1 - New benzofuran derivatives as selective 5ht7 receptor inhibitors and process for their preparation

Info

Publication number: WO2008146064A1
Application number: PCT/HU2008/000061
Authority: WO
Inventors: Ibolya Prauda; Endre RIVÓ; József Reiter; József BARKÖCZY; István GACSÁLYL; Hajnalka Kompagne; Nóra SZIRAY; Katalin Pallagi; András Egyed; Endre HEGEDÜS; György Lévay; László Gábor HÁRSING
Original assignee: Egis Gyógyszergyár
Priority date: 2007-05-30
Filing date: 2008-05-30
Publication date: 2008-12-04
Also published as: HUP0700377A2; HUP0700377A3; HU230729B1; HU0700377D0

Abstract

The present invention relates to new selective 5HT7 receptor binding benzofuran derivatives of general formula (I), wherein X represents a halogen atom or SO2NR1R2 group, wherein R1 and R2 represent, independently, a hydrogen atom, C1-6 alkyl group, C3-6 cycloalkyl group, phenyl group substituted with one or more halogen atom(s) or 1,7.7-trimethyl-bicyclo[2,2,1]hept-2-yl group, Y represents C2-6 alkylene group, optionally substituted with hydroxy group, A represents carbon atom, nitrogen atom or CH group, B represents CH or CH2 group, Q represents C1-4 alkyl group, a phenyl group optionally substituted with one or more halogen atom(s), C1-4 alkoxy group or trifluoromethyl group; phenylamino group substituted with a halogen atom or trifluoromethyl group; pyridine heterocycle; benzisoxazole or benzisothiazole heterocycle, optionally substituted with a halogen atom; benzimidazole or benzimidazolone heterocycle, optionally substituted with a halogen atom or trifluoromethyl group on the benzene ring, or optionally substituted on one of the N atoms with an C1-4 alkyl group; benzodioxane heterocycle, optionally substituted with a halogen atom on the benzene ring; pyridazinone heterocycle substituted with a halogen atom; dibenzothiazepine heterocycle or Q together with groups A and B represents a thiophene ring and their pharmaceutically suitable acid addition salts, with the proviso that if Y represents 2-hydroxy propylene group, A represents a carbon atom, B represents CH group, and Q represents 3-trifluoro-methyl-phenyl group, then X does not represent bromo atom. The invention extends to the process for producing said compounds, to pharmaceutical compositions containing said compounds and to their use in treatment and/or prevention of disorders of the central nervous system and cardiovascular system.

Description

λ

NEW BENZOFURAN DERIVATIVES AS SELECTIVE 5HT₇ RECEPTOR INHIBITORS AND PROCESS FOR THEIR PREPARATION

The invention relates to new, selective 5HT₇ receptor inhibitors of general formula (I), pharmaceutical formulations containing the same as active ingredients and a process for the preparation thereof. The new compounds are effective in the treatment of 5HT₇ receptor relating disorders, and for the treatment and/or prevention of disorders of the central nervous system and cardiovascular system.

More specifically, the invention relates to selective 5HT₇ receptor binding benzofuran derivatives of general formula (I),

(I) wherein X represents a halogen atom or

SO₂NR¹R² group, wherein

R¹ and R² represent, independently, a hydrogen atom, C_1-6 alkyl group, C_3-6 cycloalkyl group, phenyl group substituted with one or more halogen atom or l,7.7-trimethyl-bicyclo[2,2,l]hept-2-yl group,

Y represents C_2-6 alkylene group, optionally substituted with hydroxy group, A represents carbon atom, nitrogen atom or CH group, B represents CH or CH₂ group, Q represents C_1-4 alkyl group, a phenyl group optionally substituted with one or more halogen atom(s), C_1-4 alkoxy group or trifluoromethyl group; X phenylamino group substituted with a halogen atom or trifluoromethyl group; pyridine heterocycle; benzisoxazole or benzisothiazole heterocycle, optionally substituted with a halogen atom; benzimidazole or benzimidazolone heterocycle, optionally substituted with a halogen atom or trifluoromethyl group on the benzene ring, or optionally substituted on one of the N atoms with a C_1-4 alkyl group; benzodioxane heterocycle, optionally substituted with a halogen atom on the benzene ring; pyridazinone heterocycle substituted with a halogen atom; dibenzothiazepine heterocycle or

Q together with groups A and B represents a thiophene ring and their pharmaceutically suitable acid addition salts, with the proviso that if Y represents 2-hydroxy propylene group, A represents a carbon atom, B represents CH group, and Q represents 3-trifluoro-methyl-phenyl group, then X is not bromo atom.

According to the literature certain furan carboxylic amides have antidepressant properties [Yakugaku Zasshi 97 (5), 540 (1977); C.A., 87. 152125d (1997)], while benzofuran derivatives having amino, amidino, thiocarboxamidino or dialkylaminoalkyl substituents on the furan ring are H₂ receptor antagonists, and, consequently, possess an antiulcer effect [published PCT application No. 86 02550. C.A., 105, 226586U (1986)].

Tetrahydro-naphthoxy derivatives having hypotensive activity are known from published German patent application No. 22 35 597. The chemical structure of the known compounds resembles to the benzofuran derivatives of general formula

(I).

International Patent Application No. WO99/58527 describes novel benzofuran derivatives, pharmaceutical preparations containing the same and the process for the preparation thereof. The novel compounds have physiological effect on the cardiovascular system, on the heart and the nervous system through the 5HT_1A receptors. International Patent Application No. WO2002/034754 relates to benzoxazinone-derivatives, having a similar structure to the subject of the present invention. The compounds are used in the treatment and prevention of the disorders of the central nervous system, especially in the treatment and prevention of anxiety and depression.

The aim of the present invention is to prepare novel benzofuran derivatives effective in the treatment of 5HT₇ receptor related disorders of the central nervous system and/or cardiovascular system.

A huge number of 5-HT₇ receptors are located on those parts of the brain, which are responsible for the regulation of mood and cognitive functions. These areas are the thalamus, the hypothalamus and the hippocampus (Neumaier, J.F et al. 2001, Gustafson E.L. et al., 1996). Lot of antipsychotics and antidepressants used in the medication show very strong affection to the centrally located 5-HT₇ receptors (Plassat J.L. et al. 1993, Roth B.L. et al. 1994). The above results of the literature is clear that 5-HT₇ ligands are applicable for the treatment of central nervous disorders. It was found that the compounds of general formula (I) are selective inhibitors of the 5-HT₇ receptors. This unique receptor profile allows the application of the compounds of the present invention in the disorders, arising from disorders of the central nervous system and/or medical disorders such as the disorders of the heart, cardiovascular system or the kidneys.

The above aim can be reached by the new selective 5HT₇ receptor binding benzofuran derivatives of general formula (I),

(1) wherein

X represents a halogen atom or

SO₂NR . l¹rIC>2 group, wherein k

R¹ and R² represent, independently, a hydrogen atom, C_1-6 alkyl group, C_3-6 cycloalkyl group, phenyl group substituted with one or more halogen atom or

1 ,7,7-trimethyl-bicyclo[2,2,l]hept-2-yl group,

Y represents C_2-6 alkylene group, optionally substituted with hydroxy group, A represents carbon atom, nitrogen atom or CH group, B represents CH or CH₂ group, Q represents C_1-4 alkyl group, a phenyl group optionally substituted with one or more halogen atom(s), C_1-4 alkoxy group or trifluoromethyl group; phenylamino group substituted with a halogen atom or trifluoromethyl group; pyridine heterocycle; benzisoxazole or benzisothiazole heterocycle, optionally substituted with a halogen atom; benzimidazole or benzimidazolone heterocycle, optionally substituted with a halogen atom or trifluoromethyl group on the benzene ring, or optionally substituted on one of the N atoms with a C_1-4 alkyl group; benzodioxane heterocycle, optionally substituted with a halogen atom on the benzene ring; pyridazinone heterocycle substituted with a halogen atom; dibenzothiazepine heterocycle or

Q together with groups A and B represents a thiophene ring and their pharmaceutically suitable acid addition salts, with the proviso that if Y represents 2-hydroxypropylene group, A represents a carbon atom, B represents CH group, and Q represents 3-trifluoro-methyl-phenyl group, then X is not bromo atom.

The definition of the substituents is detailed below.

In the description and claims a halogen atom is primarily fluoro, chloro, bromo or iodo atom, preferably fluoro, chloro or bromo atom.

A C_1-6 alkyl group represents methyl, ethyl, n-propyl, izopropyl, n-butyl, sec- butyl, tert-butyl, izobutyl, n-pentyl or n-hexyl group, preferably methyl or isopropyl group. A C_3-6 cycloalkyl group represents cyclopropyl, cyclobutyl, cylopentyl or cyclohexyl group, preferably cyclopropyl group.

A C_2-6 alkylene group optionally substituted with hydroxyl group represents ethylene, propylene, butylene, pentylene, hexylene, or 2-hidroxy-propylene group, preferably ethylene, propylene, butylene, or 2-hidroxy-propylene group.

A C_1-4 alkyl-group represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, isobutyl group, preferably methyl group.

A phenyl group optionally substituted with one or more halogen atoms represents 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3- chloro-phenyl, 4-chloro-phenyl, 2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 3,5-dichloro-phenyl group, preferably 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro- phenyl, 2,3-dichloro-phenyl, or 3,5-dichloro-phenyl group.

A phenyl group optionally substituted with a C_1-4 alkoxy group or trifluoromethyl group represents 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy- phenyl, 2-trifluoro-methyl-phenyl, 3-trifluoro-methyl-phenyl, 4-trifluoro-methyl- phenyl, 2-methoxy-5-trifluoromethyl-phenyl group, preferably 3-methoxy-phenyl, 3-trifluoro-methyl-phenyl, or 2-methoxy-5-trifluoro-methyl-phenyl group.

A phenylamino group substituted with halogen atom, or trifluoro-methyl group represents 2-fluoro-phenylamino, 3-fluoro-phenylamino, 4-fluoro- phenylamino, 2-chloro-phenylamino, 3-chloro-phenylamino, 4-chloro-phenylamino, 2-bromo-phenylamino, 3-bromo-phenylamino, 4-bromo-phenylamino, 2-trifluoro- methyl-phenylamino, 3 -trifluoro-methyl-phenylamino, 4-trifluoro-methyl- phenylamino group, preferably 4-chloro-phenylamino, or 3-trifluoromethyl- phenylamino group.

A benzisoxazole or benzisothiazole heterocycle optionally substituted with halogen atom represents benzisoxazol-3-yl, 5-fluoro-benzisoxazol-3-yl, 6-fluoro- benzisoxazol-3-yl, 7-fluoro-benzisoxazol-3-yl, 5-chloro-benzisoxazol-3-yl, 6- chloro-benzisoxazol-3-yl, 7-chloro-benzisoxazol-3-yl, 5-bromo-benzisoxazol-3-yl, 6-bromo-benzisoxazol-3-yl, 7-bromo-benzisoxazol-3-yl, benzisothiazol-3-yl, 6- fluoro-benzisothiazol-3 -yl, 6-chloro-benzisothiazol-3 -yl, 6-bromobenziso-thiazol-3 - yl group, preferably 6-fluoro-benzisothiazol-3-yl and benzisothiazol-3-yl group. G

A benzimidazole or benzimidazolone heterocycle, optionally substituted with a halogen atom or a trifluoro-methyl group represents 4-fluoro-benzimidazol-l-yl, 5- fluoro-benzimidazol- 1 -yl, 6-fluoro-benzimidazol- 1 -yl, 7-fluoro-benzimidazol- 1 -yl, 4-chloro-benzimidazol- 1 -yl, 5-chloro-benzimidazol- 1 -yl, 6-chloro-benzimidazol- 1 - yl, 7-chloro-bezimidazol-l-yl, 4-bromo-benzimidazol-l-yl, 5-bromo-benzimidazol- 1-yl, 6-bromo-benzimidazol-l-yl, 7-bromo-bezimidazol-l-yl, 4-trifluoro-methyl- benzimidazol-1-yl, 5-trifluoro-methyl-benzimidazol-l-yl, 6-trifmoro-methyl-benz- imidazol- 1 -yl, 7-trifluoro-methyl-benzimidazol- 1 -yl, 2,3 -dihydro-2-oxo-benz- imidazol- 1 -yl, 2,3 -dihydro-2-oxo-4-fluoro-benzimidazol- 1 -yl, 2,3 -dihydro~2-oxo-5- fluoro-benzimidazol- 1 -yl, 2,3-dihydro-2-oxo-6-fluoro-benzimidazol- 1 -yl, 2,3 - dihydro-2-oxo-7-fluoro-benzimidazol- 1 -yl, 2,3 -dihydro-2-oxo-4-chloro-benz- imidazol-1-yl, 2,3-dihydro-2-oxo-5-chloro-benzimidazol-l-yl, 2,3-dihydro-2-oxo-6- chloro-benzimidazol- 1 -yl, 2,3 -dihydro-2-oxo-7-chloro-benzimidazol- 1 -yl, 2,3 - dihydro-2-oxo-4-bromo-benzimidazol-l-yl, 2,3-dihydro-2-oxo-5-bromo-benz- imidazol- 1 -yl, 2,3 -dihydro-2-oxo-6-bromo-benzimidazol- 1 -yl, 2,3 -dihydro-2-oxo-7- bromo-benzimidazol-1 -yl, 2,3-dihydro-2-oxo-4-trifluoro-methyl-benzimidazol-l -yl, 2,3-dihydro-2-oxo-5-trifluoro-methyl-benzimidazol-l-yl, 2,3-dihydro-2-oxo-6-tri- fluoro-methyl-benzimidazol-1-yl, 2,3-dihydro-2-oxo-7-trifluoro-methyl-benz- imidazol-1-yl group, preferably 5-fluoro-benzimidazol-l-yl, 6-fluoro-benzimidazol- 1-yl, 5-chloro-benzimidazol-l-yl, 6-chloro-benzimidazol- 1-yl, 2,3-dihydro-2-oxo- benzimidazol-l-yl, 2,3-dihydro-2-oxo-5-fluoro-benzimidazol-l-yl, 2,3-dihydro-2- oxo-6-fluoro-benzimidazol- 1 -yl, 2,3 -dihydro^-oxo-S-chloro-berizimidazol- 1 -yl, 2,3-dihydro-2-oxo-6-chloro-benzimidazol-l-yl, 2,3-dihydro-2-oxo-5-trifluoro- methyl-benzimidazol-1-yl group.

A benzimidazolone heterocycle optionally substituted on an N atom represents 2,3-dihydro-2-oxo-3-methyl-benzimidazol-l -yl, 2,3-dihydro-2-oxo-3- ethyl-benzimidazol- 1 -yl, 2,3 -dihydro-2-oxo-3 -propyl-benzimidazol- 1 -yl, 2,3- dihydro-2-oxo-3-izopropyl-benzimidazol-l-yl, 2,3-dihydro-2-oxo-3-butyl-benz- imidazol-1-yl, 2,3 -dihydro-2-oxo-3-isobutyl-benzimidazol- 1-yl group, preferably 2,3 -dihydro-2-oxo-3 -methyl-benzimidazol- 1 -yl group.

A benzodioxane heterocycle, optionally substituted with a halogen atom on the benzene ring represents benzodioxan-5-yl, 6-fluoro-benzodioxan-5-yl, 7-fluoro- benzodioxan-5-yl, 8-fruoro-benzodioxan-5-yl, 6-chloro-benzodioxan-5-yl, 7-chloro- benzodioxan-5-yl, 8-chloro-benzodioxan-5-yl, 6-bromo-benzodioxan-5-yl, 7-bromo- benzodioxan-5-yl, 8-bromo-benzodioxan-5-yl group, preferably benzodi-oxan-5-yl, or 7-chloro-benzodioxan-5-yl group.

A pyridazinone heterocycle substituted with a halogen atom represents A- fluoro-2,3 -dihydro-2H-pyridazin-3 -on-5-yl, 4-chloro-2,3 -dihydro-2H-pyridazin-3 - on-5-yl, 4-bromo-2₅3-dihydro-2H-pyridazin-3-on-5-yl, 6-fluoro-2,3-dihydro-2H- pyridazin-3 -on-5-yl, 6-chloro-2,3-dihydro-2H-pyridazin-3-on-5-yl, 6-bromo-2,3- dihydro-2H-pyridazin-3 -on-5-yl group, preferably 4-chloro-2,3-dihydro-2H- pyridazin-3 -on-5-yl group.

Q together with groups A and B forms a thiophene ring, which represents 4,5,6.7-tetrahidro-tieno[3,2-c]pyridin-5-yl group.

A pharmaceutically suitable acid addition salts is an acid addition salt formed with an inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid etc., or with an organic acid such as acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid etc.

The invention includes any possible isomers of the compounds of the formula I and the mixtures thereof.

A preferred subgroup of selective 5HT₇ receptor binding benzofuran derivatives of the invention consists of the benzofuran derivatives of general formula (I),

(I) wherein

X represent chloro atom or bromo atom or SO₂NR¹R² group, wherein

R¹ and R² represent, independently, a hydrogen atom, C_1-3 alkyl group, phenyl group substituted with one or two chloro atoms or bromo atom or l,7.7-trimethyl-bicyclo[2,2,l]hept-2-yl group,

Y represents C_2-4 alkylene group, optionally substituted with hydroxy group, A represents carbon atom, nitrogen atom or CH group, B represents CH- or CH₂-group, Q represents methyl group; phenyl group optionally substituted with one or two chloro atoms or fluoro atom, methoxy group or trifluoromethyl group; phenylamino group optionally substituted with chloro atom or trifluoromethyl group; pyridine heterocycle; benzisoxazole or benzisothiazole heterocycle, optionally substituted with a fluoro atom; benzimidazole or benzimidazolone heterocycle, optionally substituted with chloro atom, fluoro atom, trifluoromethyl group on the benzene ring, or substituted with a methyl group on a nitrogen atom; benzodioxane heterocycle, optionally substituted with a chloro atom on the benzene ring; pyridazinone heterocycle substituted with a chloro atom; dibenzothiazepine heterocycle or

Q together with groups A and B forms a thiophene ring and their pharmaceutically suitable acid addition salts, with the proviso that if Y represents 2-hydroxy propylene group, A represents a carbon atom, B represents CH group, and Q represents 3-trifluoro-methyl-phenyl group, then X is not bromo atom.

The especially preferred benzofuran derivatives of general formula (I) are the following: l-(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-2- oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl] -propane, l-[(2,3-Dihydro-2₅2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-5- fluoro-2-oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl]-propanehydrochloride, l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-5- chloro-2-oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl] -propane, 3 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-7- chloro- 1 ,4-benzodioxan-5 -yl)-piperazin- 1 -yl] -propane, l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2₅3-dihydro-5- fluoro-2-oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl] -propan-2-ol, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(4-chloro- phenyl)~piperazin- 1 -yl] -propane, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2₅3-dihydro-2- oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl] -propane-hydrochloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-5- fluoro-2-oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl] -propane, l-[(5-Bromo-2,3-dihydro-2₅2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-7- chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane-dihydrochloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[(2,3-dihydro-7- chloro- 1 ,4-benzodioxan-5 -yl)-piperazin- 1 -yl] -butane-dihydrochloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-(6-fluoro- benzisoxazol-3 -yl)-piperidin- 1 -yl] -butane, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-2- oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol-hydrochloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(6-fluoro- benzisoxazol-3 -yl)-piperidin- 1 -yl] -proρan-2-ol,

1 - [(5 -Bromo-2,3 -dihy dro-2,2-dimethyl-benzofuran-7-yl)-oxy] -3 - [4-(3 -chloro- phenyl)-piperazin- 1 -yl] -propan-2-ol, l-{[(5-N-isopropyl-sulfonamido)-2,3-dihydro-2₅2-dimethyl-benzofuran-7-yl]-oxy}-

3-[4-(2,3-dihydro-6-chloro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propane and pharmaceutically suitable acid additional salts thereof.

A further subject of the invention is a process for the preparation of general formula (I) and pharmaceutically suitable acid additional salts thereof, wherein Y represents C_2-6 alkylene group, X₅ A, B and Q represent a substituent as defined in claims 1 to 3 which is characterized by reacting a halid of general formula (II), wherein X represents a substituted as defined for general formula (I), Y represents C_2-6 alkylene group, Hal represents a halogen atom with a secondary amine of general formula (IV), wherein A, B and Q represent a substituent as defined for general formula (I). Another process for the preparation of general formula (I) and pharmaceutically suitable acid additional salts thereof, wherein Y represents C_2-6 alkylene group substituted with a hydroxyl group, X, A, B and Q represent a substituent as defined in claims 1 to 3 characterized by reacting an epoxide of a general formula (III), wherein X represents as defined in general formula (I), with a secondary amine of general formula (IV)₅ wherein A, B and Q represent a substituent as defined in general formula (I)₅ and if desired reacting an obtained base of the general formula (I) with an inorganic or organic acid to form a pharmaceutically suitable acid additional salt thereof, or it is liberated from the acid addition salt with a base.

A halide compound of general formula (H)₅ wherein X represents a halogen atom, Y represents C₂.₆ alkylene group, Hal represents halogen atom, is prepared by a method known from the literature [in International Patent Application No. WO 99/58527]. 7-acetoxy-2,2,dimethyl-benzofuran of formula (V)

(V) is halogenated on the aromatic ring and the obtained halo-acetoxy-derivative of general formula (VI)

(VI) wherein X represents a halogen atom, is desacetylated; and the obtained phenol of general formula (VII),

M

(VII) wherein Hal represents a halogen atom is reacted with a suitable α-₅ ω- dihalo alkane of formula (VIII),

HaI - Y - Hal¹ (VIII) wherein Hal and Hal' represent a halogen atom, which is a different or a same halogen, Y represents as defined above.

A halide compound of general formula (II), wherein X represents a SO₂NR¹R² group, R*and R² represent as defined above in formula (I), Y represents C_2-6 alkylene group, Hal represents halogen atom, is prepared by a method known from the literature [in International Patent Application No. WO 99/58527]. 7- acetoxy-2,2,dimethyl-benzofuran of formula (V)

(V) is sulfonated on the aromatic ring and the obtained sulfonic acid derivative of formula (IX)

(IX) is halogenated on the sulfonyl group, obtaining the sulfonyl chloride of formula (X)

(X) and the compound of formula (X) is reacted with a suitable secondary amine of formula (XI)

HNR1R² (XI) wherein R and R represent as defined above in general formula (I), and the obtained sulfonamido-phenol derivative of general formula (XII)

(XII) wherein R and R represent a group as defined above is reacted with the suitable α-, ω-dihalo-alkane of general formula (VIII),

HaI - Y - Hal¹

(VIII) wherein Hal and Hal' represent a halogen atom, which is a different or a same halogen, Y represents a group as defined above.

In addition the subject matter of the present invention are novel compounds of formula (IX), (X) and (XII).

The preparation of the halo-acetoxy-derivative of general formula (VI), wherein X represents a halogen atom, is carried out by the halogenation of the aromatic ring of 7-acetoxy-2,2,dimethyl-benzofuran of formula (V), in acetic acid with the suitable N-halo-succinimide at 40-80 C⁰, preferably at 60 C⁰. The isolation from the reaction mixture of the obtained compounds of general formula (VI), wherein X represents a halogen atom, is carried out by known methods, for example by dilution with water and neutralization and thereafter extraction with a water immiscible solvent and evaporation of the diluent.

Phenols of general formula (VII), wherein Hal represents a halogen atom, are prepared by desacetylation of the suitable halo-acetoxy-derivative of general formula (VI), wherein X represents a halogen atom, in methanol in the presence of an inorganic alkali-metal hydroxyde, inorganic alkali-metal carbonate, or trialkylamin, preferably sodium hydroxide, sodium carbonate or triethylamine at 0 and 60 C⁰, preferably between 20 and 30 C⁰. The isolation of the obtained phenol of general formula (VII), wherein Hal represents a halogen atom, is also carried out by a known method, for example by acidifying the reaction mυcture^'andTifterihg the^" precipitated product.

The reaction of phenols of general formula (VII), wherein Hal represents a halogen atom, and α-, ω- dihalo alkanes of general formula (VIII), wherein Hal and Hal' represent a same or a different halogen atom, Y represents C_2-6 alkylene group, is carried out in water or in a water-miscible organic solvent, preferably in alcohol, or dimethoxy ethane, or a mixture of them in the presence of an acid binding agent at a temperature between 20 and 80 C⁰, preferably between 20 C⁰ and the boiling point. A tertiary ammonium salt, preferably tetraethyl-butyl-ammonium-sulfate or triethyl-benzyl-ammonium-chloride can be used as catalyst. An alkali alcoholate, preferably sodium methylate, alkali hydroxide, preferably sodium-, or potassium hydroxide can be used as acid binding agent. The obtained compounds of general formula (II), wherein X, Y and Hal represent as defined above, can be isolated from the reaction mixture with known methods, for example the organic solution is evaporated with vacuum distillation, the residue is purified by recrystallization, the residue is subjected to a partition between water and a water immiscible organic solvent, the obtained organic phase is evaporated then the residue is recrystallized.

The sulfonylation of the aromatic ring of 7-acetoxy-2,2,dimethyl-benzofuran of formula (V) is carried out in acetic anhydride with concentrated sulfuric acid at a temperature between 0 and 40 C⁰, preferably at room temperature. The obtained sulfonic acid derivatives of general formula (IX) can be separatated with filtration.

The sulfonic acid derivatives of general formula (IX) is reacted with phosphor pentachloride at a temperature between 10 and 40 C⁰, preferably between 5 and 30 C⁰ to obtain the sulfonic acid chlorides of formula (X). The product can be separated by the method known from the literature, the residue is subjected a partition between water and a water-immiscible solvent and the obtained organic phase is evaporated.

The reaction of sulfonic acid chlorides of formula (X) and secondary amines of formula (XI), wherein R¹ and R² are as defined in general formula (I), is carried out in an inert solvent, preferably in alcohol, more preferably in methanol or ethanol at a temperature between 0 and 65 C⁰, preferably between 0 C⁰ and room temperature. The obtained compounds of general formula (VI), wherein X represents SO₂NR¹R² group, wherein R¹ and R² represent as defined above, if desired are separated by a method known from the literature or are hydrolized with an alkali metal carbonate, preferably with sodium carbonate or with ammonium hydroxide in alcohol, preferably in methanol, or ethanol. By hydrolysing the suitable phenol derivative of general formula (XII), wherein R¹ and R² represent a substituent as defined above, can be obtained.

The epoxides of general formula (III) are prepared by the reaction of phenols of general formula (VII) or sulfonamido phenol derivatives of general formula (XII) and the oxiranyl alkyl halogenides of general formula (XIII), wherein AIk represents C_1-4 alkyl group, Hal represents a halogen atom, in the presence of an alkali metal hydroxide, preferably sodium hydroxide. The reaction is carried out in the presence of an acid binding agent, water or a water-miscible organic solvent, preferably dimethoxyethane at a temperature between 20 and 60 C⁰, preferably at 40 C⁰. The endproduct can be separated by a method known from the art, by filtration or if the product is not in crystalline form in the reaction mixture, then the residue is subjected a partition between water, and water-immiscible solvent, the obtained organic phase is evaporated and the product is crystallized.

A further subject of the invention is a pharmaceutical composition comprising as active ingredient one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof together with one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

Pharmaceutical compositions of the present invention comprise a therapeutically effective dose of one or more compounds of general formula (I) and/or pharmaceutically suitable acid additional salts thereof and one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

The pharmaceutical compositions containing compounds of general formula (I) and/or pharmaceutically suitable acid additional salts thereof are suitable for peroral, parenteral (including subsutaneos, intramuscular and intravenous mode of administration), buccal, sublingual, nasal or rectal administration or for local treatment, and can be in solid or liquid form. The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and optionally comprise binding agents such as gelatine, sorbitol, polyvinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, polyethylene glycol, silica etc.; wetting agents such as sodium laurylsulfate etc.

The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e. g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.

Typical parenteral compositions consising of a solution or suspension of the compound of formula (I) and/or and/or pharmaceutically suitable acid additional salts thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions of the present invention for nasal administration containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof may conveniently be formulated as aerosols, drops, gels and powders.

Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in a single or multidose quantities in sterile form is a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon. The administraction of aerosol dosages can also take the form af a pump-atomiser. Compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof are suitable for buccal or sublingual administration including tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerol etc.

Compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

Compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof for transdermal administration include ointments, gels and patches.

Dosage forms listed above as well as other dosage forms are known per se, see e. g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).

The pharmaceutical compositions of the invention are prepared by admixing a selective 5HT₇ receptor binding benzofuran derivative of general formula (I) or a pharmaceutically suitable acid addition salt thereof to one or more carrier (s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e. g. Remington's Pharmaceutical Sciences.

The pharmaceutical compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a benzofuran derivative of formula (I) or a pharmaceutically suitable acid addition salt thereof. The amount of the active ingredient mixed with the suitable carrier, which is for one administration can be different depending on the treated recipient or on the route of administration.

The typical dosage for adult patients is 0,1-20 mg of a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof, which can ^•If be administered once or portions. The actual dose depends on many factors for example: the age, sex, weight or general health condition of the patient etc.

A further subject of the invention use of a pharmaceutical composition comprising as active ingredient a therapeutically effective dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts for the treatment and prevention of 5HT₇ receptor relating disorders of the central nervous system and/or cardiovascular disorders.

In addition the invention relates to the use of one or more compounds of general formula (I) as defined above and/or pharmaceutically suitable acid additional salts thereof, in the manufacture of a medicament for the prevention and/or treatment of 5HT₇ receptor relating disorders of the central nervous system and/or cardiovascular disorders.

Furthermore our invention relates to a method of treatment, administering for a patient suffering from 5HT₇ receptor relating disorders, especially disorders of the central nervous system and/or cardiovascular disorders a non-toxic dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof.

It has been found that the compounds of the invention, namely compounds of general formula (I) are selective 5-HT₇-receptor antagonists. This unique receptor profile makes possible the use of the compounds in the treatment of such diseases, which have in the background disorders of the central nervous system and/or some other internal disorders, such as problems of the heart-circulatory system, or diseases of the kidney.

Thus, it is expected that the compounds of the invention are well suited for the prevention and/or treatment of the following disorders of the mental and cardiovascular system such as depression, the different types of anxiety (such as Generalized Anxiety Disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia), schizofrenia, schizoaffective disorder, different mood disorders, psychosomatic disorders (for example hypertonia, stomach ulcer etc.), catastrophes of the brain, cell death on a defined area of the central nervous system, mental disorders caused by the cell deaths of the brain (pi.: Alzheimer disease, stroke, dementias etc.), disorders of the circadian rhythm and sleep disorders.

We emphasize that among the cardiovascular disorders, the compounds of the present invention in the treatment of hypertonia are effective.

The following experiments demonstrate the physiological effectiveness of the compounds of the present invention.

Receptor binding tests

5-HT₁A receptors are prepared from different region of the brain of Wistar- rats with a body weight of 20-200 g. 5-HT₇ receptors are human cloned receptors. The protein content of the membrane preparations were defined according to the method of Lo wry (1951). The following table contains the basic data of the receptor binding:

Compounds having less than 30 nM Ki are demonstrated in Table I. -13 Table I.

According to the above results it can be stated, that the compounds of general formula (I) have selective binding affinity to the central 5-HT₇ receptors, but do not show strong considerable affinity to the central 5-HT_1A receptors.

The invention is further elucidated by means of the following Examples without restricting the scope of the present invention to the Examples. Example 1

a/ 7-Acetoxy-2,3-dihydro-2,2-dimethyl-5-chloro-benzofuran

To a solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran (51.5 g, 0.25 mol) and glacial acetic acid (500 ml) iV-chloro-succinimide (50.74 g, 0.38 mol) is added under stirring, and the reaction mixture is stirred for 5 hours at 60 C⁰. The solution is evaporated in vacuum for 1/3 part and under stirring water (100 ml) is added. Under cooling the reaction mixture is neutralized with a solution of sodium hydroxide (20 %). The product is extracted with ether (2 xl50 ml), and the united solutions are washed with water, dried with anhydrous sodium sulfate, filtered and evaporated in vacuum. To the residue a solution of «-hexane and cyclohexane in a ratio of 9:1 is added and the obtained product crystals is filtered and washed with the above solution. After drying 49.6 g (82 %) of the title product are obtained. Melting point: 6O-65C⁰.

b/2,3-Dihydro-2,2~dimethyl-7-hidroxy-5-chloro-benzofuran

A suspension of 7-acetoxy-2,3-dihydro-2,2-dimethyl-5-chloro-benzofuran (19.32 g, 0.08 mol) and methanol (60 ml) is cooled to 10 C⁰ and under cooling and stirring 80 ml of sodium hydroxide (20 w/v%) is added at a temperature between 10 and 18 C⁰. The reaction mixture is stirred at 10 C⁰ for half an hour and the methanol is evaporated under vacuum. The pH of the residue is adjusted to pH = 3-4 with a solution of hydrochloric acid (10 %) under cooling and stirred for another 10 minutes. The obtained crystals are filtered, washed and dried. Thus, 13.4 g (84 %) of the title product are obtained. Melting point: 61-64 C⁰.

Example 2 a/ J-Acetoxy^S-dihydro^^-dimethyl-benzofuranS-sulfonic acid

To a solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran (20.6 g, 0.1 mol) and acetic anhydride (40 ml) is added under stirring at a temperature of 0-5 C⁰ and Xi

within half an hour a cold prepared solution of cc. sulphuric acid (6 ml, 0.1 mol) and acetic anhydride (20 ml) is added dropwise and the reaction mixture is stirred for another half an hour at the same temperature. The solution is diluted with acetone (150 ml), cooled to 10 C⁰, and the pH of the solution is adjusted to pH=3-4 with a dropwise added solution of sodium hydroxide (8 ml, 40 w/v %) at the same temperature. The obtained crystals are filtered, washed with cold acetone and dried. Thus, 25.3 g (~ 88 %) of the title product are obtained. Melting point: 160-170 C⁰.

b/7-Λcetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonyl chloride

7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonic acid (11.45 g, 0.04 mol) in powdery form is cooled to -5 C⁰ in a dry ice/acetone cooling bath under stirring and thereafter quickly phosphor pentachloride (25.0 g, 0.12 mol) is added thereto. Meanwhile the temperature of the solution rises to 34 C⁰. The reaction mixture is cooled to 10-15 C⁰ and stirred for 2 hours at this temperature, then dichloromethane (30 ml) is added under stirring and cooling, and it is decomposed by adding water (30 ml) dropwise. Thereafter by adding sodium hydroxide solution (65 ml, 40 w/v %) dropwise under continuous cooling and stirring the reaction mixture is neutralized, the phases are separated and the aqueous phase is extracted with 2 x 30 ml of dichloromethane. The united organic phases are dried with anhydrous sodium sulfate, filtered, and evaporated in vacuum. The obtained crystal product is mixed with diisopropyl ether (20 ml), filtered and washed with cold diisopropyl-ether. Thus, 6.45 g (53 %) of the title product are obtained. Melting point: 95-98 C⁰.

Example 3 2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid amide

To the solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonyl chloride (7.62 g, 0.025 mol) and acetonitrile (25 ml) under stirring ammonia gas (4.25 g, 0.025 mol) is added in a bomb tube in a dry ice/acetone cooling bath. The reaction mixture is stirred for 2 hours at 5-10 C⁰ and evaporated in vacuum after removing from the bomb tube. To the residue methanol (30 ml) and cc. aqueous ammonium hydroxide (4 ml) are added and the solution is boiled for two hours. The methanol is evaporated in vacuum and the obtained crystals of the title compound are washed in isopropanol (20 ml), filtered and washed with cold isopropanol and dried. The yield of the title compound is 4.75 g (78 %). Melting point: 216-220 C⁰.

Example 4

2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid-N-methyl-amide

To a solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonyl chloride (24.38 g, 0.08 mol) and ethanol (80 ml) ethanolic methylamine ( 20 ml), 15.06 g, 0.16 mol, 33 w/v%) solution is added in a bomb tube in a dry ice/acetone cooling bath. The reaction mixture is stirred for 3 hours at 5-10 C⁰ and evaporated in vacuum after removing from the bomb tube. Thus, 2,3-dihydro-2,2-dimethyl-7- acetoxy-benzofuran-5 -sulfonic acid-iV-methyl-amide (30.05 g) is obtained, which is directly used without purification in the following steps of the reaction. To the residue methanol (80 ml) and cc. aqueous ammonium hydroxide (10 ml) is added and boiled for two hours. The methanol is evaporated in vacuum from the reaction mixture and the residue is divided between dichloromethane (40 ml) and water (10 ml) and the phases are separated. The aqueous layer is extracted with dichloromethane (20 ml), the organic layers are united and dried over anhydrous sodium sulfate, filtered and evaporated in vacuum. The obtained crystals of the title compound are mixed with ethyl acetate (20 ml), filtered and washed with cold ethyl acetate and dried. Thus, 4.83 g (29 %) of the title product are obtained. Melting point: 184-188 C⁰.

Example 5

2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-S-sulfonic acid-N-isopropyl- amide

To a solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonyl chloride (7.92 g, 0.026 mol) and ethanol (80 ml) under stirring and cooling isopropylamine JLb

(4.5 ml, 3.07 g, 0.052 mol) is added dropwise at 0 C⁰ and the reaction mixture is stirred for one hour at a temperature between 0 — 5 C⁰. The solution is evaporated in vacuum and the residue is divided between chloroform (30 ml) and water (25 ml) and the aqueous phase is extracted with chloroform (20 ml). The organic phases are united and dried over anhydrous sodium sulfate, filtered and evaporated in vacuum. Thus, 6.1 g (82,3 %) thickly flowing title product are obtained. ¹H-NMR (CDCl₃):δ, ppm 7.31 m (IH), 7.25 m (IH), 4.6 b (IH), 4.10 m (IH), 3.06 s (2H), 1,14 s (6H), 1,08 s (6H).

Example 6

2,3-Dihydro-2,2-dimethyl-7-acetoxy-benzofuran-5-sulfonic acid-N-cyclopropyl- amide

To a solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonyl chloride (3.05 g, 0.01 mol) and ethanol (20 ml) under stirring and cooling cyclopropylamine (1.4 ml, 1,14 g, 0.02 mol) is added dropwise at 0 C⁰, and thereafter the reaction mixture is stirred for two hours at a temperature between 0 and 5 C⁰. The solution is evaporated in vacuum and the residue is divided between dichloromethane (15 ml) and water (15 ml) and the pH of the solution is adjusted to pH=6 with hydrochloric acid solution (10 w/w%). After separating the two phases the aqueous phase is extracted with dichloromethane (20 ml). The united solutions of dichloromethane are dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum. Thus, 1.49 g (45.8 %) thickly flowing title product are obtained. ¹H-NMR (CDCl₃): δ, ppm 7.55 m (IH), 7.48 m (IH), 4.7 b (IH), 3.10 s (2H), 2.32 s (3H), 2.27 m (IH), 1.52 s (6H), 0.62 m (4H).

Example 7

2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid-N-[4-(3-chloro- phenyl)-piperazin-l-yl]-amide JM a/ 7-Acetoxy-2,3-dihydro~2,2-dimethyl-benzofuran-5-sulfonic acid-N-[4-(3-chloro- phenyl)-piperazin-l-yl]-amide

To the solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonic acid- chloride (7.62 g, 0.025 mol) and ethanol (50 ml) the solution of 4-(3-chloro-phenyl)- piperazine (9.83 g, 0.05 mol) and ethanol (50 ml) was added dropwise under stirring and cooling at 0 C⁰ then the reaction mixture is stirred for two hours at a temperature between 0 and 5 C⁰. The precipitated crystals are filtered and washed with ethanol. The crystals are divided between hydrochloric acid (30 ml), 1 v/w %) and dichloromethane (60 ml), the phases are separated and the organic phase is dried over anhydrous sodium sulfate, filtered and evaporated until dry. The residue in crystalline form is mixed with diisopropyl ether, filtered and washed with diisopropyl ether and dried. Thus, 8.42 g (72.4 %) of the title product are obtained. Melting point: 176-185 C⁰.

b/2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid-N-[4-(3- chloro-phenyl)-piperazin-l-yl]-amide

A mixture of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5 -sulfonic acid-iV-[4- (3-chloro-phenyl)-piperazin-l-yl]-amide (7.44 g, 0.016 mol), methanol (50 ml) and anhydrous sodium carbonate (2.01 g, 0.019 mol) is stirred for 28 hours at room temperature. The reaction mixture is dried in vacuum, the residue is divided between dichloromethane (50 ml) and water (50 ml), the phases are separated, and the aqueous phase is extracted with dichloromethane (20 ml). The united organic phases are dried over anhydrous magnesium sulfate, filtered and dried in vacuum. The obtained crystalline oily product is mixed with diisopropyl ether, filtered, washed with diisopropyl ether and dried. Thus, 5.67 g (83.8 %) of the title product are obtained. Melting point: 176-180 C⁰. Example 8

2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid-N-(3,4-dichloro- phenyl)-amide

a/7-Acetoxy-2,3-dihydro-2,2-dimethyI-benzofuran-5-sulfonic acid-N-(3,4- dichloro-phenyl)-amide

To the solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonic acid chloride (9.14 g, 0.03 mol) and methanol (50 ml) 3,4-dichloro-aniline (10.69 g, 0.066 mol) is added dropwise at room temperature under stirring, and the reaction mixture is stirred for two hours. The precipitated crystals of the reaction mixture is filtered, washed with methanol and dried. Thus, 10.0 g (77 %) of the title product are obtained. Melting point: 180-185 C⁰.

b/2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid-N-(3,4- dichloro-phenyl)-amide

The mixture of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzofuran-5-sulfonic acid-N- (3,4-dichloro-phenyl)-amide (9.47 g, 0.022 mol), methanol (50 ml) and ammonium hydroxide (5 ml, 25 %) are boiled for one and a half an hour. The obtained solution is evaporated in vacuum, and the residue is divided between chloroform (40 ml), ethanol (10 ml) and water (40 ml), the phases are separated and the chloroformic phase is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum. The precipitated oily crystals of the reaction mixture are mixed with diisopropyl ether, filtered, washed with diisopropyl ether and dried. Thus, 7.3 g (85.5 %) of the title product are obtained. Melting point: 197-200 C⁰.

Example 9

2,3-Dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid-N-(lR-l, 7.7- trimethyl-bicyclo[2.2.1]hept-2-yl)-amide To the solution of 7-acetoxy-2,3-dihydro-2,2-dimethyl-benzotøan-5-sulfonyl chloride (7.62 g, 0.025 mol) and methanol (40 ml) under stirring at room temperature (li?)-(l,7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amine (4.60 g, 0.03 mol) and anhydrous sodium carbonate (3.18 g, 0.03 mol) are added, and the reaction mixture is stirred for 5.5 hours on an oil bath at 48 C⁰. The obtained reaction mixture is evaporated in vacuum and the residue is divided between chloroform (25 ml), ethanol (2 ml) and water (20 ml) and the phases are separated. The aqueous phase is extracted with chloroform (15 ml). The united phases of chloroform are dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum. Thus, 9.2 g (87.3 %) thickly melting title product are obtained, which can be used directly in the following steps of the reaction.

Example 10 2,3-Dihydro-2,2-dimethyI-5-chloro-7-(3-chloro-propoxy)-benzqfuran

To 60 ml of absolute methanol under stirring sodium methylate (4.86 g, 0.09 mol), 2,3-dihydro-2,2-dimethyl-7-hydroxy-5-chloro-benzofuran (15.89 g, 0.08 mol) and 1- bromo-3-chloro-propane (15.74 g, 10.2 ml, 0.1 mol) are added and the reaction mixture is boiled for another 3 hours under stirring. From the obtained reaction mixture methanol is evaporated in vacuum and to the residue dichloromethane (50 ml) and water (50 ml) are added. The phases are separated and the aqueuos phase is extracted with dichloromethane (50 ml). The united solution of dichloromethane are extracted with water (2 x 50 ml) and with sodium hydroxide solution (1 x 50 ml), 1 w/v%), dried over anhydrous sodium sulfate, filtered, and evaporated until dry. To the obtained oily product «-hexane (50 ml) is added and evaporated again. To the obtained residue of evaporation petroleum ether (20 ml) is added and the title product is obtained in crystalline form, which is filtered, washed with petroleum ether and dried. Yield: 12.6 g (57.2 %). Melting point: 43-45 C⁰.

Example 11 2,3-Dihydro-2,2-dimethyl-S-chloro-7-(oxiranyl-methoxy)-benzofuran A solution of sodium hydroxide (4.0 g, 0.1 mol) and water (200 ml) is cooled to 5 C⁰ and under stirring 2,3-dihydro-2,2-dimethyl-7-hydroxy-5-chloro-benzofuran (17.88 g, 0.09 mol) is added. The reaction mixture is stirred for 5 minutes under cooling, and under continuous stirring and cooling a solution of epichlorohydrine (16.66 g, 14 ml, 0.18 mol) and 1,2-dimethoxyethane (40 ml) is added dropwise for 15 minutes. The reaction mixture is warmed to 40 C⁰ and the strirring is continued at the same temperature for 2 hours. The obtained reaction mixture is extracted with dichloromethane (2 x 100 ml) and the unified organic solutions are washed with water (2 x 50 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry. Thus, 21,3 g (92.9 %) thickly flowing title product are obtained. The title product forms crystals with isopropanol. The crystals are filtered, washed with isopropanol and dried. Thus, 7.71 g (33.6 %) of the title product are obtained. Melting point: 49-51 C⁰. The mother solution is evaporated until dry and the residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of petroleum ether and dichloromethane in different ratios. By this step a further 11,4 g (49.7 %) of the title product are obtained. Melting point: 48-50 C⁰.

Example 12 5-Bromo-2,3-dihydro-2,2-dimethyl-7-(2-Bromo-ethoxy)-benzofuran

To a solution of sodium hydroxide (2.28 g, 0.057 mol) and water (27 ml) tetrabutyl ammonium hydrogensulfate (0.17 g, 0.0005 mol), 1 ,2-dibromoethane (8.8 ml, 19.25 g, 0.1025 mol) and 2,3-dihydro-2,2-dimethyl-7-hidroxy-5-bromo-benzofuran (10.0 g, 0.041 mol) are added at room temperature under stirring, and the reaction mixture is boiled for 24 hours under stirring. After cooling the reaction mixture is diluted with dichloromethane (40 ml) and the phases are separated, the organic phase is dried over anhydrous sodium sulfate, filtered and evaporated until dry. Thus, 10.1 g oily title product are obtained, which can be directly used for the next steps of the synthesis. ¹H-NMR (CDCl₃): δ, ppm 6.90 s (IH), 6.85 s (IH), 4.06t (2H), 3.58 t (2H), 2.99 s (2H), 1,48 s (6H). SL8

Example 13 5-Bromo-2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran

To 2,3-dihydro-2,2-dimetliyl-7-hydroxy-5-bromo-benzofuran (24.3 g, 0.1 mol) under stirring at room temperature aqueous sodium hydroxide (100 ml, 10 w/v %), l-bromo-3-chloro-propane (14.8 ml, 23.6 g, 0.15 mol), dichloromethane (100 ml) and triethylbenzyl-ammonium chloride (1.0 g) are added, and the reaction mixture is stirred at 40 C⁰ for four hours. After cooling the reaction mixture is diluted with water (100 ml) and with dichloromethane (50 ml) the phases are separated and the aqueous phase is extracted with dichloromethane (50 ml). The united solutions of dichloromethane are extracted with sodium hydroxide(100 ml, 1 N) and with water (2 x 100 ml), filtered, and the residue is dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. Thus, 13.57 g (42.4 %) of the title product are obtained, which is purified with vacuum distillation. Bp: 148.5 C°/2.3 Hgmm. Yield: 7.3 g (22.8 %), oily title product, which forms crystals under storage. The melting point of the product crystallized with «-hexane is 43-45 C⁰.

Example 14 5-Bromo-2,3-dihydro-2,2-dimethyl-7-(4-Bromo-butoxy)-benzofuran

To a solution of 2,3-dihydro-2,2-dimethyl-7-hydroxy-5-bromo-benzofuran (18.4 g, 0.0756 mol) under stirring at room temperature aqueous sodium hydroxide (75 ml, 10 w/v %), 1,4-dibromo-butane (24.3 g, 0.11 mol), dichloromethane (75 ml) and triethyl-benzylammonium chloride (0.75 g) are added and the reaction mixture is stirred at 40 C⁰ for four hours. After cooling the reaction mixture is diluted with water (200 ml) and with dichloromethane (50 ml), the phases are separated and the aqueous phase is extracted with dichloromethane (50 ml). The united solutions of dichloromethane is extracted with sodium hydroxide (150 ml, 1 N) and with water (2 x 150 ml), filtered, and the residue is dried over anhydrous sodium sulfate, filtered again, the anhydrous sodium sulfate is washed with dichloromethane (20 ml) and the solutions of dichloromethane are united, and evaporated until dry in vacuum. To the obtained crystals H-hexane (100 ml) is added, filtered and the residue is evaporated until dry in vacuum. Thus, 22.7 g oily product are obtained, which is distilled in vacuum, Bp: 150-160 C71.5 Hgmm. Yield: 15.65 g (54.7 %), oily title product, which forms crystals under storage. The melting point of the product crytallized with rc-hexane is 38.5-39 C⁰.

Example 15 2,3-Dihydro-2,2-dimethyl-7-(3~chloro-propoxy)-benzofuran-5-sulfonic acid-amide

To a solution of absolute methanol (150 ml) under stirring sodium methylate (7.56 g, 0.14 mol), 2,3-dihydro-2,2-dimethyl-7-hidroxy-benzofuran-5-sulfonic acid amide (14.6 g, 0.06 mol) and l-bromo-3-chloro-propane (18.89 g, 12.3 ml, 0.12 mol) are added and the reaction mixture is boiled under stirring for 14 hours. From the obtained reaction mixture methanol is evaporated in vacuum, the residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of rø-hexane and dichloromethane in different ratios. After evaporation 5.1 g (26.6 %) crystalline title product are obtained. Melting point: 188-192 C⁰.

Example 16 2,3-Dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran-5-sulfonic acidamide

A solution of sodium hydroxide (2.64 g, 0.066 mol) with water (160 ml) is cooled to 2 C⁰, and under stirring 2,3-dihydro-2,2-dimethyl-7-hydroxy-benzofuran-5-sulfonic acidamide (14.6 g, 0.06 mol) is added to the solution. The reaction mixture is stirred for 5 minutes under stirring and with continuous cooling and stirring a solution of epichlorohydrine (11,1 g, 9.41 ml, 0.12 mol) with 1 ,2-dimethoxyethane (30 ml) is added dropwise for 15 minutes. The reaction mixture is warmed at 40 C⁰, and at the same temperature the reaction mixture is stirred for 4.5 hours. The precipitated product is filtered, washed with water and dried. Thus, 7.8 g (43 %) title compound are obtained. Melting point: 208-211 C⁰. Example 17

2,3-Dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5-sulfonic acid-N- methyl-amide

In methanol (5 ml) sodium methylate (0.28 g, 5.3 mmol) is dissolved under stirring and the solution is cooled to a temperature between 0 and 5 C⁰ and at the same temperature 2,3 -dihydro-2,2-dimethyl-7-hydroxy-benzofuran-5 -sulfonic acid-iV- methyl-amide (0.9 g, 0.0035 mol) and l-bromo-3-chloro-propane (0.37 ml, 0.57 g, 0.0036 mol) are added and the reaction mixture is boiled for 40 hours under stirring. After cooling chloroform (10 ml), water (5 ml), ethanol (2 ml) are added to the reaction mixture, the phases are separated and the aqueous phase is extracted with chloroform (10 ml). The united solution of chloroform is dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus, 0.72 g (61.6 %) oily title product is obtained, which forms crystals by adding diisopropyl-ether (5 ml) and ethylacetate (1 ml). After filtering 0.6 g (51,3 %) of the title product are obtained in crystalline form. Melting point: 110-113 C⁰.

Example 18

2,3-Dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5-sulfonic acid-N- isopropyl-amide

To the solution of 2,3-dihydro-2,2-dimethyl-7-hydroxy-benzofuran-5-sulfonic acid- JV-isopropyl amide (2.00 g, 0.007 mol) a solution of potassium hydroxide (0.46 g, 0.007 mol) with ethanol (85 %, 10 ml) is added dropwise under stirring at room temperature then l-bromo-3-chloro-propane (0.7 ml, 1,10 g, 0.007 mol) is also added. The reaction mixture is stirred for two hours. Then the ethanol is evaporated in vacuum and the residue is divided between dichloromethane (20 ml), chloroform (5 ml) and water (15 ml), separated and the aqueous phase extracted with the mixture of dichloromethane (20 ml) and ethanol (6 ml). The united phases are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus, 2.1 g (82.9 %) of title compound are obtained in crystalline form. The melting point M of the product crystallized with the solution of diisopropyl and ethylacetate in a ratio of l5 : l is 93-96 C°.

Example 19

2,3-Dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5-sulfonic acid-N- cyclopropyl-amide

To 2,3 -dihydro-2,2-dimethyl-7-hydroxy-benzofuran-5-sulfonic acid-iV-cyclopropyl- amide (5.66 g, 0.02 mol) a solution of potassium hydroxide (1.45 g, 0.022 mol) with ethanol (85 %, (30 ml) is added dropwise at room temperature under stirring then 1- bromo-3-chloro-propane (2.3 ml, 0.022 mol) is also added. The reaction mixture is stirred for two hours. Then the ethanol is evaporated in vacuum and the residue is divided between chloroform (40 ml) and water (40 ml), separated and the aqueous phase is extracted with the mixture of dichloromethane (20 ml) and ethanol (15 ml). The united phases are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus, 7.7 g of the oily title compound are obtained. Then diisopropyl-ether (30 ml) and ethylacetate (6 ml) are added to the product and the obtained crystalline product is filtered and dried. Thus, 3.5 g (48.6 %) of the title product are obtained. Melting point: 125-129 C⁰.

Example 20

2,3-Dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5-sulfonic acid-N-[4-

(3-chloro-phenyl)-piperazin-l-yl]-amide

To 2,3-dihydro-2,2-dimethyl-7-hydroxy-benzofuran-5-sulfonic acid-iV-[4-(3-chloro- phenyl)-piperazin-l-yl] -amide (4.65 g, 0.011 mol) under stirring at room temperature a solution of potassium hydroxide (0.67 g, 0.012 mol) with ethanol (85 %, 25 ml) is added dropwise then l-bromo-3-chloro-propane (1.2 ml, 1,89 g, 0.012 mol) is also added. The reaction mixture is stirred for three hours. Then the ethanol is evaporated in vacuum and the residue is divided between dichloromethane (20 ml), ethanol (15 ml) and water (20 ml), then it is separated and the aqueous phase is extracted with dichloromethane (20 ml). The united phases are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus, 3.7 g (67.3 %) of the title product are prepared in crystalline form, which is mixed with ethyl acetate (10 ml), filtered and dried. Thus, 3.3 g (60.1 %) of the title product are obtained. Melting point: 148-151 C⁰.

Example 21

2,3-Dihydro-2,2-dimethyU7-(2-chloro-ethoxy)~benzofuran-5-sulfonic acid-N~(3,4- dichloro-phenyl)-amide

In absolute methanol (15 ml) sodium methylate (0.64 g, 0.012 mol) is dissolved and the solution under stirring is cooled to 0-5 C⁰. At this temperature 2,3-dihydro-2,2- dimethyl-7-hydroxy-benzofuran-5 -sulfonic acid-iV-(3 ,4-dichloro-phenyl)-amide (3.49 g, 0.009 mol) and l-bromo-2-chloro-ethane (1,72 g, 0.012 mol) are added. The reaction mixture is boiled under stirring for 30 hours. After cooling dichloromethane (50 ml) and water (10 ml) are added to the reaction mixture, the precipitated inorganic salts are filtered, the phases are separated, the organic phase is washed with water (10 ml), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuum until dry. Thus, 1.85 g oily title product are obtained, which is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and petroleum ether in different ratios. The suitable fractions are united and evaporated and 1.27 g (31.3 %) of the pure title product are obtained. Melting point: 138-142 C⁰

Example 22

2,3-Dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5-sulfonic acid-N-

(3,4-dichloro-phenyl)-amide

In absolute methanol (15 ml) sodium methylate (0.64 g, 0.012 mol) is dissolved under stirring and the solution is cooled to 0-5 C⁰. At this temperature 2,3-dihydro- 2,2-dimethyl-7-hydroxy-benzofuran-5-sulfonic acid-N-(3,4-dichloro-phenyl)-amide (3.49 g, 0.009 mol) and l-bromo-2-chloro-propane (1.57 g, 0.01 mol) are added. The reaction mixture is boiled under stirring for 17 hours. Then methanol, used as a solvent, is evaporated in vacuum and the residue is divided between water (10 ml) and dichloromethane (20 ml), the phases are separated, and the aqueous phase is extracted with dichloromethane (20 ml). The united organic phases are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The obtained crystalline product is mixed with ethyl acetate, filtered again and dried. Thus, 2.02 g (48.2 %) of the pure title product are prepared. Melting point: 132-136 C⁰.

Example 23

2,3-Dihydro-2,2-dimethyl-7-(2-chloro-ethoxy)-benzofuran-5-sulfonic acid-N-(lR- 1, 7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide

In absolute methanol (40 ml) under stirring sodium methylate (1.92 g, 0.035 mol) is dissolved, and the solution is cooled to 0-5 C⁰. At this temperature 2,3-dihydro-2,2- dimethyl-7-hydroxy-benzofuran-5-sulfonic acid-N-(lR-l,7.7-trimethyl- bicyclo[2.2.1]hept-2-yl)-amide (10.54 g, 0.025 mol) and l-bromo-2-chloro-ethane (4.30 g, 0.03 mol) are added to the reaction mixture, and it is boiled for 65 hours under stirring. After cooling methanol is evaporated in vacuum from the reaction mixture, and to the residue dichloromethane (30 ml) and water (10 ml) are added, the phases are separated, the organic phase is extracted with aqueous hydrochloric acid (10 ml, 1 %), dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. Thus, 7.22 g oily title product is obtained, which is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of di-chloromethane and n-hexane in different ratios. The suitable fractions are united and evaporated and to the residue diisopropyl ether is added and the product is filtered. Thus, 4.00 g (36.2 %) of the pure title product are obtained. Melting point: 152-157 C⁰.

Example 24

2,3-Dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-S-sulfonic acid-N- (IR-1, 7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide 3J^

In absolute methanol (15 ml) sodium methylate (0.65 g, 0.012 mol) is dissolved under stirring, and the solution is cooled to 0-5 C⁰. At this temperature 2,3-dihydro- 2,2-dimethyl-7-hydroxy-benzofuran-5-sulfonicacid-iV-(lR-l,7.7-trimethyl-bi- cyclo[2.2.1]hept-2-yl)-amide (3.37 g, 0.008 mol) and l-bromo-3-chloro-propane (1.2 ml, 1.89 g, 0.012 mol) are added. The reaction mixture is boiled under stirring for 11 hours. Then methanol, used as a solvent, is evaporated in vacuum and the residue is divided between water (15 ml) and dichloromethane (20 ml), the phases are separated and the aqueous phase is extracted with dichloromethane (10 ml). The unified organic phases are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the obtained oily product diisopropyl ether (10 ml) is added. The product, which is in crystalline form, is filtered, washed with diisopropyl ether and dried. Thus, 1.60 g (43.8 %) of the pure title product are obtained. Melting point: 125-130 C⁰.

Example 25 l-[(2,3-Dihydw-2,2-dimethyl-5-chlom-henzofuran-7-yl)-oxy]-3-[4-(3-trifluoro- methyl-phenyl)-l,2,5,6-tetrahydro-pyridin-l-yl]-propane-hydrochloride

In absolute methanol (40 ml) sodium methylate (1.21 g, 0.022 mol) is dissolved at room temperature under stirring. To the solution 2,3-dihydro-2,2-dimethyl-5-chloro- 7-(3-chloro-propoxy)-benzofuran (4.26 g, 0.015 mol) and 4-(3-trifluoro-methyl- phenyl)-l,2,5,6-tetrahidro-pyridine (3.96 g, 0.015 mol) are added and the reaction mixture is boiled for 30 hours under stirring. Then methanol is evaporated in vacuum from the reaction mixture, and a mixture of dichloromethane (25 ml) and chloroform (25 ml) is added to the residue. The solution is extracted with hydrochloric acid (20 ml, 5 w/v%), with sodium hydrocarbonate (25 ml, 5 w/v %) and with water (2 x 20 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol as eluent, in different ratios and the suitable fractions are evaporated in vacuum. Thus, 2.8 g (40.9 %) pure, title base is obtained, which is dissolved in ethylacetate (10 ml) and a solution of absolute hydrochloric acid in isopropanol (2 ml 25 w/v %) is added to the solution. The obtained hydrochloric acid salt of the title product is filtered, washed with ethyl acetate and dried. Thus, 1.8 g (25.7 %) of the title product are obtained. Melting point: 192-197 C⁰.

Example 26 l-[(2,3-Dihydro~2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(6-chloro- benzimidazole-l-yl)-piperidin-l-yl]-propan

The powdery mixture of 2,3-dihydro-2,2-dimethyl-5-chloro-7-(3-chloro-propoxy)- benzofuran (1.38 g, 0.005 mol), 4-(6-chloro benzimidazole-l-yl)-piperidine (1.07 g, 0.0055 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) is put in an oil bath warmed in advance to 140 C⁰ and reacted for 6 hours under stirring. After cooling the brown, resinous reaction mixture is divided between ethylacetate (20 ml) and water (15 ml), the phases are separated, and the aqueous phase is extracted with ethyl acetate (10 ml). The united solutions of ethylacetate are dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual brown, oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as an eluent a mixture of dichloromethane and methanol in different ratios. After the suitable fractions are evaporated, 1.35 g (56.9 %) of the title product is obtained, which is mixed with diisopropyl ether, filtered and dried. Thus, 0.83 g (35.0 %) of the pure title product are obtained. Melting point: 113-116 C⁰.

Example 27 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro~2- oxo-benzintidazoJe-l-yl)-piperidin-l-yl]-propan

A mixture of 2,3-dihydro-2,2-dimethyl-5-chloro-7-(3-chloro-propoxy)-benzofuran (0.28 g, 0.001 mol), 4-(2,3-dihydro-2-oxo-benzimidazol-l-yl)-piρeridine (0.29 g, 0.001 mol), triethylamin (3 ml) and iV-methyl-pyrrolidone (3 ml) is put in an oil bath warmed in advance to 140 C⁰ and stirred for 13 hours. After cooling to the reaction mixture water (5 ml) and ethylacetate (6 ml) are added and the pH of the solution is adjusted to pH=6 with hydrochloric acid (0.1 N), the phases are separated, the organic phase dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product isopropanol is added and the obtained crystals are filtered. Thus, 0.32 g (70.2 %) of the title product are obtained. Melting point: 179-181 C⁰. .

Example 28 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofumn-7-yl)-oxy]-3-[4-(2,3-dihydro-5- fluoro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propane-hydrochloride

The powdery mixture of 2,3-dmydro-2,2-dimethyl-5-chloro-7-(3-chloro-propoxy)- benzofuran (1.32 g, 0.0048 mol), 4-(2,3-dihydro-5-fluoro-2-oxo-benzimidazol-l-yl)- piperidine (1.18 g, 0.005 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) is put in an oil bath warmed in advance to 140 C⁰ and stirred for 4 hours. After cooling, the reaction mixture is divided between water (10 ml) and ethylacetate (15 ml), the phases are separated, and the organic phase is extracted with hydrochloric acid (2 x 10 ml, 1 w/v %) and with water (15 ml). The phase with ethylacetate is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. Thus, 1.78 g (81,3 %) of the oily product are obtained, which is crystallized with acetonitrile (10 ml). The crystals are filtered, washed with acetonitrile and thus 1.28 g (58.5 %) of the pure title product are obtained. Melting point: 234-240 C⁰.

Example 29 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)~oxy]-3-[4-(2,3-dihydro-6- chloro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propane

The procedure of Example 27 is followed with the difference that the reaction is carried out with 0.004 moles of 4-(2,3-dihydro-6-chloro-2-oxo-benzimidazol-l-yl)- piperidine instead of 4-(2,3-dihydro-2-oxo-benzimidazol-l-yl)-piperidine, and the reaction is completed under warming for 20 hours. The reaction mixture is processed according to the example 27, and thus 2.48 g of the oily product are obtained, whiuch is crystallized with the mixture of ethylacetate (15 ml) and acetonitrile (1 ml). Thus, 0.85 g (43 %) of the pure title product are obtained. Melting point: 180-182 C⁰.

Example 30 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-5- chloro-2-oxo~benzimidazol~l-yl)-piperidin-l-yl]-propan

To a mixture of dimethylformamide (4 ml) and triethylamine (1,38 ml, 1,00 g, 0.001 mol) potassium iodide (1.16 g, 0.007 mol), 4-(2,3-dihydro-5-chloro-2-oxo- benzimidazol-l-yl)-piρeridine (1.77 g, 0.007 mol) and 2,3-dihydro-2,2-dimethyl-5- chloro-7-(3-chloro-propoxy)-benzofuran (2.56 g, 0.008 mol) are added and the reaction mixture is stirred for 20 hours at 120 C⁰. After cooling, water (10 ml) is added to the reaction mixture to obtain crystalline product. After stirring for 8 hours, the crystals are filtered, washed with water and dried. Thus, 2.3 g (67 %) of the product obtained, which is crystallized in hot acetonitrile (45 ml). The precipitated pure title product is filtered and washed with acetonitrile. Yield: 1.5 g (43.7 %). Melting point: 165-167 C⁰.

Example 31 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-2- oxoS-trifluoro-methyl-benzimidazol-l-y^-piperidin-l-ylJ-propane-hydrochloride

The powdery mixture of 2,3-dihydro-2,2-dimethyl-5-chloro-7-(3-chloro-propoxy)- benzofuran (0.77 g, 0.0028 mol), 4-(2,3-dihydro-2-oxo-5-trifluoro-methyl- benzimidazol-l-yl)-piperidine (0.86 g, 0.003 mol) and anhydrous sodium carbonate (0.35 g, 0.0033 mol) is put in an oil bath warmed in advance to 140 C⁰ and stirred for 2 hours. After cooling, the reaction mixture is divided between water (10 ml) and ethylacetate (15 ml), the phases are separated, the organic phase is extracted with a solution of hydrochloric acid (1 x 10 ml, 1 w/v %). The phase of ethyl acetate is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. 0.85 g (54.2 %) of the crystalline product are obtained. This product is crystallized in a mixture of acetonitrile (5 ml) and ethyl acetate (10 ml). Thus, 0.57 g (36.3 %) of the pure title product are obtained. Melting point: 139-142 C⁰.

Example 32 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-3- methyl-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propane

The procedure of Example 31 is followed with the difference that 4-(2,3-dihydro-3- methyl-2-oxo-benzimidazol-l-yl)-piperidine (0.69 g, 0.003 mol) was used instead of 4-(2,3-dihydro-2-oxo-5-trifluoro-methyl-benzimidazol-l-yl)-piperidine.The reaction mixture is processed according to the Example 31. Thus, 0.88 g (62.0 %) of the crystalline product are obtained, which is crystallized from acetonitrile (10 ml). Thus, 0.71 g (50.0 %) of the pure, title compound are obtained. Melting point: 139- 141 C⁰.

Example 33 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(4-chloro- phenyl-amino)-piperidin-l-yl]-propane

The mixture of 2,3-dihydro-2,2-dimethyl-5-chloro-7-(3-chloro-propoxy)-benzofuran (1.10 g, 0.004 mol), 4-(4-chloro-phenyl-amino)-piperidine (0.88 g, 0.0042 mol), triethylamin (10 ml) and JV-methyl-pirrolidon (1,5 ml) is put in an oil bath warmed in advance to 120 C⁰ and stirred for 16 hours. After cooling, the reaction mixture is divided between dichloromethane (20 ml) and water (15 ml), the pH of the mixture is adjusted to pH=3 with hydrochloric acid solution (5 w%), the phases are separated and to the organic phase water (5 ml) is added, alkalised with sodium hydroxide (1 N, pH = 9), the phases are separated, the phase with dichloromethane is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual 2.1 g oily product are dissolved in diisopropyl ether (15 ml) and crystallized. The crystals are filtered, washed with diisopropyl ether and dried. Thus, 0.9 g (50.1 %) of the title product are obtained. The melting point of the product 33

- crystallized in the solution of diisopropyl ether and ethylacetate in a ratio of 9 : 1 - is 115-119 C⁰.

Example 34 l-[(2,3-Dihydro-2,2~dimethyl-5-chloro-benzofuran-7-yl)~oxy]-3-[4~(3-trifluoro- methyl-phenyl-amino)-piperidin-l-yl]-propane

A mixture of 2,3-dihydro-2,2-dimethyl-5-chloro-7-(3-chloro-propoxy)-benzofuran (1,10 g, 0.004 mol), 4-(3-trifluoro-methyl-phenyl-amino)-piperidine (1.07 g, 0.0044 mol), triethylamin (10 ml) and JV-methyl-pyrrolidone (0.6 ml) is put in an oil bath warmed in advance to 120 C⁰ and stirred for 13 hours. After cooling, the reaction mixture is divided between dichloromethane (20 ml) and water (20 ml), the pH of the mixture is adjusted to pH=3 with hydrochloric acid solution (5 w%), the phases are separated and to the organic phase water (5 ml) is added, alkalized with sodium hydroxide (I N, pH = 9) and the phases are separated. The organic phase is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual oily product is dissolved in diisopropyl ether (15 ml) and crystallized. The crystals are filtered, washed with diisopropyl ether and dried. Thus, 1.7 g (88.1 %) of the title compound are obtained. The melting point of the product crystallized from diisopropyl ether is 119-122 C⁰.

Example 35 l-[(2,3-Oihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(3-chloro- phenyl)-piperazin-l-yl]-propane

In absolute ethanol (30 ml) sodium methylate (0.81 g, 0.015 mol) is dissolved under stirring at room temperature and to the solution methanol (10 ml), 2,3-dihydro-2,2- dimethyl-5-chloro-7-(3-chloro-propoxy)-benzofuran (4.12 g, 0.015 mol) and 4-(3- chloro-phenyl)-piperazine (2.95 g, 0.015 mol) are added. The reaction mixture is boiled under stirring for 25 hours, and then ethanol and methanol is evaporated in vacuum. The residue is dissolved in a mixture of dichloromethane (30 ml) and water /fO

(30 ml) and the phases are separated. The aqueous phase is extracted with dichloromethane (25 ml) and the united solvents of dichloromethane are washed with water (2 x 20 ml), extracted with hydrochloric acid solution (10 ml, 5 w/v %), with sodium hydrocarbonate (15 ml, 5 w/v %) and with water (2 x 20 ml), dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The crystallized residue (4.6 g) is mixed with ethyl acetate (15 ml), filtered and dried. Thus, 1.7 g (19.9 %) of the title product are obtained. The melting point of the product crystallized in acetonitrile is 113-118 C⁰.

Example 36 l-ftl_fS-Dihydro-I^-dimethylS-chloro-benzofuran-J-yty-oxyJS-ft-^-chloro- phenyl)-piperazin-l-yl]-propane

In a solution of water (20 ml) and isopropanol (10 ml) under stirring sodium hydroxide (0.76 g, 0.019 mol) is dissolved at room temperature and 4-chloro- phenyl-piperazine (3.34 g, 0.017 mol) and 2,3-dihydrό-2,2-dimethyl-5-chloro-7-(3- chloro-propoxy)-benzofuran (6.30 g, 0.0197 mol) are added, then the reaction mixture is boiled under stirring for 25 hours. Then isopropanol is evaporated in vacuum from the reaction mixture, the residue is divided between water (50 ml) and dichloromethane (80 ml), the phases are separated, the organic phase is extracted with water (30 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus, 6.2 g (83.7 %) of the title product are obtained, which is crystallized in hot acetonitrile (70 ml). The precipitated product is filtered, washed with acetonitrile, dried. Thus, 5.8 g (78.3 %) of the title product are obtained. Melting point: 129-13O C⁰.

Example 37 l-f(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxyJ-3-f4-(2,3-dihydro-7- chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane

The powdery mixture of 1.38 g (0.005 mol) 2,3-dmydro-2,2-dimethyl-5-chloro-7-(3- chloro-propoxy)-benzofuran, 1.53 g (0.006 mol) 4-(2,3-dihydro-7-chloro-l,4- hi benzodioxan-5-yl)-piperazine and 0.64 g (0.006 mol) anhydrous sodium carbonate is put in an oil bath warmed in advance to 150 C⁰ and stirred for 1.5 hours. After cooling, the reaction mixture is divided between water (5 ml) and ethyl acetate (15 ml), the phases are separated, the organic phase is extracted with hydrochloric acid (1 x 5 ml, 1 w/v%). The phase with ethyl acetate is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. Thus, 2.4 g oily residue are obtained, which is crystallized from isopropanole (15 ml). The crystalline product is filtered, stirred and washed with isopropanol, then dried. Thus, 1.1 g (45.6 %) of the pure title compound are obtained. Melting point: 110-114 C⁰.

Example 38 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-2- oxo-benzimidazol-l-yl)-piperidin-l-ylJ-propan-2-ol

The powdery mixture of 2,2-dimethyl-2,3-dihydro-5-chloro-7-(oxiranyl-methoxy)- benzofuran (1.18 g, 0.005 mol), 4-(2,3-dihydro-2-oxo-benzimidazol-l-yl)-piperidine (1.08 g, 0.005 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) is put in an oil bath warmed in advance to 120 Co and stirred for 13 hours. After cooling, the reaction mixture is divided between water (10 ml) and ethyl acetate (30 ml), the phases are separated, the organic phase is extracted with hydrochloric acid solution (1 x 5 ml, 1 w/v %). The phase with ethyl acetate is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. Thus, 1.78 g (75.6 %) of the crystalline title product are obtained. Melting point: 166-170 C⁰.

Example 39 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro- l,4-benzodioxan-5-yl)-piperazin-l-yl]-propan-2-ol dihydrochloride

The mixture of 2,2-dimethyl-2,3-dihydro-5-chloro-7-(oxiranyl-methoxy)-benzofuran (1.02 g, 0.004 mol), 4-(2,3-dihydro-l,4-benzodioxan-5-yl)-piperazine-hydrochloride (1.02 g, 0.004 mol), aqueous sodium hydroxide (10 ml, 1 N) and methanol (10 ml) is stirred at room temperature for 3.5 hours. After standing the solution for one night, next day it is extracted with dichloromethane (30 ml), and the phases are separated. The aqueous phase is extracted with dichloromethane (20 ml), and the united solutions of dichloromethane are extracted again with water (4 x 25 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry. The obtained foamlike product (1.66 g) is dissolved in ethyl acetate (10 ml) and hydrochloric acid in isopropanol (3 ml, 25 w/v%) is added to the solution. The precipitated crystals are filtered, washed with ether. Thus, 1,6 g (84.2 %) of the pure title compound are obtained. Melting point: 116-122 C⁰.

Example 40 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-[4-(3-trifluoro- methyl-phenyl)-l,2,5,6-tetrahidro-piridin-l-yl]-propan-2-ol-hydrochloride

The mixture of 2,2-dimethyl-2,3-dihydro-5-chloro-7-(oxiranyl-methoxy)-benzofuran (2.55 g, 0.01 mol), 4-(3-trifluoromethyl-phenyl)-l,2,5,6-tetrahydro-pyridine (2.89 g, 0.011 mol), aqueous sodium hydroxide solution (15 ml, 1 N) and methanol (5 ml) is stirred for 3 hours at room temperature. The reaction mixture is extracted with dichloromethane (100 ml), the phases are separated, the dichloromethaneous phase is extracted with water (3 x (30 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry. The residual 4.94 g oily product is dissolved in ether (50 ml), filtered, and to the residue hydrochloric acid in isopropanol (10 ml, 25 w/v %) is added. The precipitated crystals are filtered and washed with ethyl acetate. Thus, 2.41 g (47.8 %) of the pure title compound are obtained. Melting point: 142-145 C⁰.

Example 41 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]~3-[4-(2,3-dihydro-5- fluoro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol

The procedure of Example 38 is followed with the difference that the reaction is carried out in 4-(2,3-dihydro-5-fluoro-2-oxo-benzimidazol-l-yl)-piperidine (1.18 g, 0.005 mol) instead of 4-(2,3-dihydro-2-oxo-benzimidazol-l-yl)-piperidine. The reaction mixture is processed according to the Example 38, and thus 1.93 g (81 %) of the crystalline title product are obtained. Melting point: 180-186 C⁰.

Example 42 l-[(2,3~Dihydro-2,2-dimethyl-5-chloro-benzqfuran-7-yl)-oxy]-3-[4-(2,3-dihydro-6- fluoro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol-monohydrate

The mixture of 2,2-dimethyl-2,3-dihydro-5-chloro-7-(oxiranyl-methoxy)-benzofuran (1.27 g, 0.005 mol), 4-(2,3-dihydro-6-fluoro-2-oxo-benzimidazol-l-yl)-piperidine (1.17 g, 0.005 mol) and ethanol (20 ml) is stirred for 72 hours at room temperature. The reaction mixture is evaporated until dry, the residue is divided between dichloromethane (60 ml) and water (30 ml), the phases are separated, the solution with dichloromethane is extracted with water (30 ml), dried over anhydrous sodium sulfate, filtered and evaporated until dry. The residual 1.3 g (53.1 %) crystalline product is recrystallized in the solution of acetonitrile (20 ml) and methanol (10 ml). The obtained title compound is filtered, washed with the above solvent and dried. Thus, 0.9 g (36.7 %) of the pure product are obtained. Melting point: 181-183 C⁰.

Example 43 l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-2- oxo-5-chloro-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol

The mixture of 2,2-dimethyl-2,3-dihydro-5-chloro-7-(oxiranyl-methoxy)-benzofuran (2.04 g, 0.008 mol), 4-(2,3-dihydro-2-oxo-5-chloro-benzimidazol-l-yl)-piperidine (2.01 g, 0.008 mol) and ethanol (40 ml) is stirred for 72 hours at room temperature. The reaction mixture is evaporated until dry, the residue is crystallized from methanol (70 ml). The precipitated crystals are filtered, and washed with methanol. Thus, 2.35 g (58.0 %) of the pure title product are obtained. Melting point: 185- 186.5 C⁰. Example 44 l-[(2,3-Dihydro-2,2-dimethyl-S-chloro-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-3-methyl~2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol

The procedure of Example 38 is followed with the difference that the reaction is carried out with 4-(2,3-dihydro-3-methyl-2-oxo-benzimidazol-l-yl)-piperidine (1,15 g, 0.005 mol) instead of a 4-(2,3-dihydro-2-oxo-benzimidazol-l-yl)-piperidine. The reaction mixture is processed according to the Example 38, and thus 1.74 g (71.8 %) of the crystalline title product are obtained. Melting point: 153-156 C⁰.

Example 45 l-fβ^-Dihydro^^-dimethylS-chloro-benzofuran-J-yty-oxyJ-S-ft-β-chloro- phenyl)-piperazin-l-yl]-propan-2-ol

In abs. methanol (30 ml) sodium methylate (0.81 g, 0.015 mol) is dissolved at room temperature. To the solution 2,2-dimethyl-2,3-dihydro-5-chloro-7-(oxiranyl- methoxy)-benzofuran (3.82 g, 0.015 mol) and 4-(3-chloro-phenyl)-piperazine (2.95 g, 0.015 mol) are added and the reaction mixture is stirred at room temperature for 19 hours. From the reaction mixture methanol is evaporated in vacuum, the residue is divided between dichloromethane (50 ml) and water (20 ml), the phases are separated, the solution with dichloromethane is washed with water (2 x 20 ml), extracted with hydrochloric acid (10 ml, 5 w/v %), sodium hydrocarbonate (20 ml, 10 w/v %) and water (2 x 20 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. The crystallized residue (6.1 g) is mixed with acetonitrile (5 ml), filtered and dried. Thus, 4.0 g (59.0 %) of the title compound are obtained. The melting point of the product, crystallized in isopropanol is 116-120 C⁰.

Example 46 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-2-[4,5,6.7- tetrahydro-thieno[3,2,-c]piridin-5-yl]-ethane πε

To a solution of sodium hydroxide (1.6 g, 0.04 mol) and water (20 ml) under stirring 4,5,6.7-tetrahydro-thieno[3,2,-c]pyridine-hydrochloride (2.2 g, 0.02 mol) is added at room temperature and stirred for 15 minutes and then 5-bromo-2,3-dihydro-2,2- dimethyl-7-(2-bromo-ethoxy)-benzofuran (7.0 g, 0.02 mol) is added. The reaction mixture is boiled for 20 hours and after cooling the two phases of the solvent are separated by decantation, the oily phase is solved in dichloromethane (20 ml), the solvent is extracted with water (2x15 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The residual crystalline product is suspended with ether, filtered, washed with ether and dried. Thus, 2.44 g (29.9 %) of the title product are obtained. The melting point of the product crystallized from ethanol is 85-87 C⁰.

Example 47 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3-chloro- phenyl)-piperazin-l-yl]-propane-hydrochloride

To the solution of sodium hidroxide (0.4 g, 0.01 mol) and water (12 ml) under stirring at room temperature 4-(3-chloro-phenyl)-piperazine (1.96 g, 0.01 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(3-bromo-propoxy)-benzofuran (3.64 g, 0.01 mol) are added and boiled for 12 hours. After cooling the reaction mixture is extracted with dichloromethane (20 ml), the solution of dichloromethane is extracted with water (2x15 ml), dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The residual crystalline product is suspended with ether, filtered, washed with ether and dried. Thus, 4.17 g (80.8 %) of the title product are obtained. The melting point of the product, crystallized from methanol is 206-210 C⁰.

Example 48 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(4-chloro- phenyl)-piperazin-l-yl]-propane To the solution of sodium hydroxide (0.24 g, 0.006 mol) and water (8 ml) under stirring 4-(4-chloro-phenyl)-piperazine (1,18 g, 0.006 mol), and 5~bromo-2,3- dihydro-2,2-dimethyl-7-(3-bromo-propoxy)-berizofuran (2.18 g, 0.006 mol) are added at room temperature and boiled for 14 hours. After cooling the reaction mixture is extracted with dichloromethane (15 ml), and the solution of dichloromethane is extracted with water (10 ml), dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The residual crystalline product is suspended with ether, filtered, washed with ether and dried. Thus, 1,78 g (63.8 %) of the title product are obtained. The melting point of the product, crystallized from acetonitrile is 145-147 C⁰.

Example 49 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3,5-dichloro- phenyl)-piperazin-l-yl]-propane-hydrochloride-dihydrate

To the solution of sodium hydroxide (0.4 g, 0.01 mol) and water (12 ml) under stirring 4-(3,5-dichloro-phenyl)-piperazine (2.31 g, 0.01 mol), and 5-bromo-2,3- dihydro-2,2-dimethyl-7-(3-bromo-propoxy)-benzofuran (3.64 g, 0.01 mol) are added at room temperature and boiled for 10 hours. After cooling the reaction mixture is subject to decantation and the oily residue is dissolved in dichloromethane (50 ml). The solution of dichloromethane is extracted with water (20 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The residual crystalline product is suspended with ether, filtered, washed with ether and dried. Thus, 1,51 g (25.8 %) of the title product are obtained The melting point of the product, crystallized from acetonitrile is 208-211 C⁰.

Example 50 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3- trifluoroomethyl-phenyl)-l,2_t5,6-tetrahidro-pyridin-l-yl]-propane-hydrochloride

To the solution of sodium methylate (0.7 g, 0.013 mol) in absolute methanol (10 ml) under stirring l,2,5,6-tetrahydro-4-(3-trifluoromethyl-phenyl)-pyridine hydro- chloride (2.77 g, 0.007 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(3-chloro- propoxy)-benzofuran (1.92 g, 0.006 mol) are added at room temperature and the reaction mixture is boiled for 7 hours. After the reaction is terminated, the reaction mixture is evaporated until dry in vacuum, the residue is divided between dichloromethane (30 ml) and water (20 ml), the aqueous phase is extracted with dichloromethane (20 ml). The united solvents of dichloromethane are extracted with sodium hydroxide solution (30 ml) 1 N) and water (2 x (30 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The residual oily product (3.27 g) is subjected to chromatography on a column filled with Kieselgel 6OH using as an eluent a mixture of toluene and n-hexane in different ratios. After evaporating the suitable fractions 1.72 g (31.4 %) of the crystalline title compound are obtained. Melting point: 179.5-182.5 C⁰.

Example 51 l-[(5-Bromo-2,3~dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-2- oxo-benzintidazol-l-yl)-piperidin~l-yl]-propanehydrochloride

To the solution of sodium hydroxide (0.2 g, 0.005 mol) and water (6 ml) under stirring 4-(2,3-dihydro-2-oxo-benzimidazole-l-yl)-piperidine (1.08 g, 0.005 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(3-bromo-propoxy)-benzofuran (1.82 g, 0.005 mol) are added at room temperature, and boiled for 5 hours. After cooling the reaction mixture is subject to decantation, the oily residue is dissolved in dichloromethane (25 ml), the solution of dichloromethane is extracted with water (10 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (2.0 ml, 20 w %) and ether (5 ml) are added. After standing the solution in refrigerator for one night, the precipitated crystalline product is filtered, washed with ether and dried. Thus, 2.0 g (74.5 %) of the title product are obtained. The melting point of the product, crystallized from methanol is 235-238 C⁰. Example 52 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-5- fluoro-2-oxo-benzitnidazol-l-yl)-piperidin-l-yl]-propane

To the solution of triethylamine (0.4 g, 0.76 ml, 0.004 mol) and dimethylformamide (5 ml) under stirring 4-(2,3-dihydro-5-fluoro-2-oxo-benzimidazol-l-yl)-piperidine (0.47 g, 0.002 mol) and 5~bromo-2,3-dihydro-2,2-dimethyl-7-(3-bromo-ρropoxy)- benzofuran (0.72 g, 0.002 mol) are added at room temperature. The reaction mixture is put in an oil bath for 48 hours and then warmed to 80 C⁰ and stirred for 16 hours. After cooling water (30 ml) is added to the reaction mixture, it is extracted with dichloromethane (2 x (30 ml), the united solutions of dichloromethane are washed with water (20 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus, 0.82 g (86.8 %) of the title product are obtained. The melting point of the product, crystallized from ethyl acetate is 148-153 C⁰.

Example 53 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4_f5,6.7- tetrahydro-thieno[3,2,-c]piridin-5-yl]-propane-hydrochloride

To the solution of sodium hydroxide (0.8 g, 0.02 mol) and water (12 ml) at room temperature under stirring 4,5,6.7-tetrahydro-thieno[3,2,-c]pyridine-hydrochloride (1.75 g, 0.01 mol) is added, then stirred for 15 minutes and then 5-bromo-2,3- dihydro-2,2-dimethyl-7-(3-bromo-propoxy)-benzofuran (3.64 g, 0.01 mol) are added. The mixture is boiled for 10 hours, after cooling the solution with the two phases is subject to decantation, the oily phase is dissolved in dichloromethane (20 ml), the solution is extracted with water (15 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (5 ml, 20 w/w%) and ether (10 ml) are added, the crystalline product is filtered, washed with ether and dried. Thus, 2.44 g (53.1 %) of the title product are obtained. The melting point of the product, crystallized from isopropanol is 200-202 C⁰. Example 54 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane-dihydrochloride

To the solution of sodium hydroxide (0.4 g, 0.01 mol) and water (8 ml) under stirring at room temperature 4-(2,3-dihydro-l,4-benzodioxane-5-yl)-piperazin hydrochloride (1.28 g, 0.005 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(3- bromo-propoxy)-benzofuran (1.82 g, 0.005 mol) are added and the solution is boiled fo 18 hours. After cooling the solution is subject to decantation and the oily phase is dissolved in dichloromethane (15 ml), the solution is extracted with water (15 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (2.5 ml, 20 w/w%) and ether (10 ml) are added, and the crystalline product is filtered, washed with ether, and dried. Thus, 1.83 g (63.5 %) of the title product are obtained. The melting point of the product crystallized from isopropanol is 147- 151 C⁰.

Example 55 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-7-chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane- dihydrochloride

To the solution of sodium hydroxide (0.2 g, 0.005 mol) and water (6 ml) under stirring at room temperature 4-(2,3-dihydro-7-chloro-l,4-benzodioxane-5-yl)- piperazine (1.27 g, 0.005 mol) and 5-bromo-2,3-dihydro-2,2-dirnethyl-7~(3- bromo-propoxy)-benzofuran (1.82 g, 0.005 mol) are added and the mixture is boiled for 10 hours. After cooling the solution with the two phases is subject to decantation, the oily phase is dissolved in dichloromethane (20 ml), the solution is extracted with water (15 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (4.0 ml, 20 w/w %) and ether (10 ml) are added, the crystalline product is filtered, washed with ether and dried. Thus, 1.86 g (60.0 %) of the title 5X5 product are obtained The melting point of the product, crystallized from isopropanol is 133-136 C⁰.

Example 56 l-[(5-Bromo-2,3-dihydro~2,2-dimethyl-benzqfuran-7-yl)-oxy]-3-[4-(2-pyridyl)- piperazin-l-yl]-propane-dihydrochloride

To the solution of sodium hydroxide (0.4 g, 0.01 mol) and water (10 ml) under stirring at room temperature l-(2-pyridyl)-piperazine (1.63 g, 1.52 ml, 0.01 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(3-bromo-propoxy)-benzofuran (3.64 g, 0.01 mol) are added and the solution is boiled for 5 hours. After cooling the solution with the two phases is subject to decantation, the oily phase is dissolved in dichloromethane (20 ml), the solution is extracted with water (15 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (6.0 ml, 20 w/w %) and ether (10 ml) are added, the crystalline product is filtered, washed with ether and dried. Thus, 3.48 g (67.0 %) of the title product are obtained. The melting point of the product, crystallized from isopropanol is 187-190 C⁰.

Example 57 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(4-chloro-3- oxo-2H-pyridazin-5-yl)-piperazin-l-yl]-propane

To the solution of triethylamine (0.2 g, 0.28 ml, 0.002 mol) and dimethylformamide (6 ml) under stirring at room temperature potassium iodide (0.33 g, 0.002 mol), 5-bromo-2,3-dihydro-2,2-dimethyl-7-(3-bromo-ρropoxy)- benzofuran (0.73 g, 0.002 mol) and 4-(4-chloro-3-oxo-2if-pyridazin-5-yl)- piperazine (0.43 g, 0.002 mol) are added, and the the reaction mixture is stirred for 3 days. Under stirring water (30 ml) is added to the reaction mixture, and after stirring for 10 minutes the crystals are filtered, washed with water and ether and dried. Thus, 0.60 g (60.3 %) of the title product are obtained. The melting point of the product, crystallized from methanol is 181-183 C⁰. Example 58 l-[(5-Bromo-2,3-dihydro~2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-(3- trifluoromethyl-phenyl)-l, 2,5, 6-tetrahydro-pyridin-l-yl]-butane hydrochloride

To methanol (25 ml) at room temperature under stirring 4-(3-trifluoromethyl- phenyl)-l,2,5,6-tetrahydro-pyridine hydrochloride (4.43 g, 0.013 mol), sodium methylate (1.18 g, 0.022 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(4- bromo-butoxy)-benzofuran (3.78 g, 0.01 mol) are added, then the reaction mixture is boiled for 6 hours. After cooling the reaction mixture is evaporated until dry in vacuum, the residue is divided between dichloromethane (50 ml) and water (30 ml) and the phases are separated. The aqueous phase is extracted with dichloromethane (50 ml), the united organic phases are extracted with sodium hydroxide (50 ml, 5 w/v %) and with water (2 x 50 ml), dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. Thus, 5.1 g of the title product are obtained. The residual product is subjected to flash chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of toluene and ethyl acetate in different ratios. The suitable phases are evaporated, the residue is dissolved in ether (50 ml), and hydrochloric acid in isopropanol (5 ml, 25 w/w%) is added to the solution. The precipitated crystalline product is filtered and thus, 4.04 g (72.3 %) of the title compound are obtained. Melting point: 161-164 C⁰.

Example 59 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-(2,3- dihydro-l,4~benzodioxan-5-yl)-piperazin-l-yl]-butane dihydrochloride

To the solution of sodium hydroxide (0.64 g, 0.016 mol) and water (10 ml) under stirring at room temperature 4-(2,3-dihydro-l,4-benzodioxane-5-yl)-piperazine hydrochloride (2.05 g, 0.008 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(4- bromo-butoxy)-benzofuran (3.02 g, 0.008 mol) are added and the solution is boiled for 18 hours. After cooling the solution separated in two phases is subject SJL to decantation, the oily phase is dissolved in dichloromethane (20 ml), the solution is extracted with water (15 ml), dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (3.5 ml, 20w/w %) and ether (10 ml) are added, the crystalline product is filtered, washed with ether, and dried. Thus, 2.93 g (62.0 %) of the title product are obtained. The melting point of the product crystallized from isopropanol is 166-168 C⁰.

Example 60 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-methyl- piperidin-l-yl]-butane hydrochloride

To the solution of sodium hydroxide (0.32 g, 0.008 mol) and water (8 ml) under stirring at room temperature 4-methyl-piperidine (0.95 ml, 0.8 g, 0.008 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(4-bromo-butoxy)-benzofuran (3.02 g, 0.008 mol) are added and the mixture is boiled for 15 hours. After cooling to the reaction mixture dichloromethane (25 ml) and water (15 ml) are added, the phases are separated, the organic phase is extracted with water (15 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (2.0 ml, 20 w/w %) and ether (10 ml) are added, the crystalline product is filtered, washed with ether, and dried. Thus, 1.61 g (46.5 %) of the title product are obtained. The melting point of the product crystallized from acetonitrile is 155-162 C⁰.

Example 61 l-[(5-Bromo-2,3-dihydro~2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-(3-chloro- phenyl)-piperazin-l-yl]-butane hydrochloride

To the solution of sodium hydroxide (0.24 g, 0.006 mol) and water (6 ml) under stirring at room temperature 4-(3-chloro-phenyl)-piperazine (1.18 g, 0.006 mol) and 5-bromo-2,3-dihydro-2,2-dimethyl-7-(4-bromo-butoxy)-benzofuran (2.27 g, 0.006 mol) are added and the solution is boiled for 16 hours. After cooling the solution separated in two phases is subject to decantation, the oily phase is dissolved in dichloromethane (20 ml), the solution is extracted with water (15 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (5.0 ml, 20 w/w%) and ether (10 ml) are added, the crystalline product is filtered, washed with ether, and dried. Thus, 1.24 g (41.7 %) of the title product are obtained. The melting point of the product, crystallized from acetonitrile is 188-192 C⁰.

Example 62 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-(2-pyridyl)- piperazin-l-yl]-butane

To the mixture of chloroform (10 ml), sodium hydroxide (10 ml, 1 N) and triethyl-butyl-ammonium chloride (0.2 g) under stirring at room temperature 1- (2-pyridyl)-piperazine (0.65 g, 0.004 mol) and 5-bromo-2,3-dihydro-2,2- dimethyl-7-(4-bromo-butoxy)-benzofuran (1.19 g, 0.003 mol) are added. The reaction mixture is stirred at room temperature for 7 hours, then at 40 C⁰ for 5 hours, and at 60 C⁰ for 6 hours. After cooling the phases are separated, the aqueous phase is extracted with chloroform (15 ml), the united solutions of chloroform dried over anhydrous sodium sulfate, filtered, then evaporated until dry. Thus, 1.9 g of the crystalline product are obtained, which is recrystallized from isopropanol (25 ml). Yield: 0.97 g (70.3 %). Melting point: 107-110 C⁰.

Example 63 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-(4,5,6.7- tetrahydro-thieno[3,2-c]piridin-5-yl)-butane

To the mixture of chloroform (10 ml), sodium hydroxide (10 ml, 1 N) and tetra- butyl-ammonium chloride (0.2 g) under stirring at room temperature 4,5,6.7- tetrahydro-thieno[3,2-c]pyridine hydrochloride (0.70 g, 0.004 mol) and 5-bromo- 2,3-dihydro-2,2-dimethyl-7-(4-bromo-butoxy)-benzofuran (1,19 g, 0.003 mol) are added. The reaction mixture is stirred at room temperature for 8 hours, then at 40 C⁰ for 10 hours, and at 60 C⁰ for 10 hours. After cooling the phases are separated, the aqueous phase is extracted with chloroform (15 ml), the united solutions of chloroform are dried over anhydrous sodium sulfate, filtered, and evaporated until dry. Thus, 1,4 g of the crystalline product are obtained, which is recrystallized from isopropanol (15 ml). Yield 0.96 g (73.3 %). Melting point: 104-108 C⁰.

Example 64 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-henzofuran-7-yl)-oxy]-4-[(2,3~dihydro-

7-chloro-l,4-benzodioxane-5-yl)-piperazin-l-yl]-butane dihydrochloride

To the mixture of chloroform (10 ml), sodium hydroxide (17 ml, 1 N) and acetonitrile (10 ml) under stirring at room temperature (2,3-dihydro-7-chloro-l,4- benzodioxane-5-yl)-piperazine (0.76 g, 0.003 mol) and 5-bromo-2,3-dihydro-2,2- dimethyl-7-(4-bromo-butoxy)-benzofuran (1.19 g, 0.003 mol) are added, The reaction mixture is stirred for 20 hours, then at 40 C⁰ for 20 hours. After cooling the phases are separated, the aqueous phase is extracted with chloroform (15 ml), the united solutions of chloroform are dried over anhydrous sodium sulfate, filtered, and evaporated until dry. Thus, 1.55 g of the oily product are obtained. The residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of toluene and ethyl acetate in different ratios. The suitable phases are evaporated, the residue is dissolved in isopropanol (15 ml), and hydrochloric acid in isopropanol (10 ml, 25 w/w%) is added to the solution. Filtering the crystalline product, 0.69 g (41.7 %) of the pure title compound are obtained. Melting point: 133-137 C⁰.

Example 65 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-(6-fluoro~ benzisoxazol-3-yl)-piperidin-l-yl]-butane

To the mixture of 4-(6-fluoro-benzisoxazol-3-yl)-piperidine-hydrochloride (3.08 g, 0.012 mol) and isopropanol (25 ml) under stirring at room temperature sodium methylate (1.28 g, 0.024 mol) are added and stirred for 5 minutes, then 5-bromo- 2,3-dihydro-2,2-dimethyl-7-(4-bromo-butoxy)-benzofuran (3.78 g, 0.01 mol) is added to the solution and it is stirred for 10 hours at room temperature. The reaction mixture evaporated until dry, the residue is divided between water (100 ml) and dichloromethane (60 ml), the phases are separated, the aqueous phase is extracted with dichloromethane (60 ml). The solution of the united phases of dichloromethane is extracted with water (50 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry. Thus, 4.8 g thickly flowing product are obtained, which is crystallized with methanol (15 ml). The precipitated crystals are filtered, washed with methanol (5 ml) and dried. Yield: 2.3 g (44.4 %). Melting point: 108-110.5 C⁰.

Example 66 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-phenyl-l,2,5,6- tetrahydro-pyridin-l-yl]-propan-2-ol

To the mixture of 4-phenyl-l,2,5,6-tetrahydro-pyridine hydrochloride (1,95 g, 0.01 mol) and isopropanol (20 ml) under stirring at room temperature sodium methylate (0.54 g, 0.01 mol) is added and after stirring for 5 minutes, 5-bromo- 2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (2.99 g, 0.01 mol) is added and it is stirred for 5 hours at room temperature. The precipitated crystalline product is filtered, washed with isopropanol and dried. Thus 4.3 g (93.8 %) of the title compound are obtained. Melting point: 115-116 C⁰.

Example 67 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3-methoxy- phenyl)-l,2,5,6-tetrahydro-pyridin-l-yl]-propan-2-ol

To the solution of potassium hydroxide (85 %, 0.66 g, 0.01 mol) with ethanol (28 ml) under stirring at room temperature 4-(3-methoxy-phenyl)-l,2,5,6-tetrahydro- pyridine hydrochloride (2.1 g, 0.0093 mol), then 5-bromo-2,3-dihydro-2,2- dimethyl-7-(oxiranyl-methoxy)-benzofuran (2.99 g, 0.01 mol) are added, and it is stirred for 5 hours at room temperature. The reaction mixture is evaporated until dry in vacuum. The residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of rø-hexane and chloroform in different ratios. The suitable phases are evaporated (3.9 g, 85.8 %) of the title compound are obtained. The melting point of the product, crystallized from isopropanol is 83-85 C⁰.

Example 68 l-[(S-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-2- oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol-hydrochloride

To the solution of ethanol (8 ml) under stirring at room temperature 4-(2,3- dihydro-2-oxo-benzimidazol-l-yl)-piperidine (0.85 g, 0.0034 mol), then 5- bromo-2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (1.0 g, 0.0034 mol) are added, and then solution is stirred for 48 hours at room temperature. The reaction mixture is evaporated until dry in vacuum, the residue is dissolved in chloroform (10 ml), to the solution hydrochloric acid in isopropanol (2.0 ml, 20 w/v%) is added, then evaporated again until dry in vacuum. The crystalline residue is suspended with ether, filtered and washed with ether. Thus, 1.76 g (93.6 %) of the title compound are obtained. The melting point of the product, crystallized from isopropanol is 233-236 C⁰.

Example 69 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-5- fluoro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol-hydrochloride

To the solution of ethanol (10 ml) under stirring at room temperature 4-(2,3- dihydro-5-fluoro-2-oxo-benzimidazol-l-yl)-piperidine (1,17 g, 0.005 mol), then 5-bromo-2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (1.5 g, 0.005 mol) are added, and the reaction mixture is stirred for 5 hours at room temperature, then it is boiled for 3.5 hours. The reaction mixture is evaporated until dry in vacuum, the residue is suspended in ether (10 ml), filtered, and washed with ether. Thus, 1.34 g of the crystalline product are obtained, which is dissolved with hydrochloric acid in isopropanol (15 ml, 20 w/v %), and the solution is crystallized with ether (10 ml). The precipitated crystals are filtered, washed with ether. Thus, 1.34 g (46.9 %) of the title compound are obtained. The melting point of the product, crystallized from isopropanol is 206-210 C⁰.

Example 70 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(6-fluoro- benzisoxazol-3-yl)-piperidin~l-yl]~propan-2-ol

To the mixture of 4-(6-fluoro-benzisoxazol-3-yl)-piperidine (2.57 g, 0.012 mol) and isopropanol (20 ml) under stirring at room temperature sodium methylate (0.54 g, 0.012 mol) is added, it is stirred for 5 minutes, then 5-bromo-2,3- dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (2.99 g, 0.01 mol) is added to the solution and stirring is continued for 2 hours at room temperature. The precipitated crystalline product is filtered, and washed with isopropanol. Thus, 4.35 g (78.2 %) of the title compound are obtained. The melting point of the product, crystallized from isopropanol is 119-121 C⁰.

Example 71 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-(4,5,6.7- tetrahydro-thieno[3,2-c]pyridin-5-yl)-propan-2-ol-hydrochloride

To the solution of ethanol (8 ml) under stirring at room temperature 4,5,6.7- tetrahydro-thieno[3,2-c]pyridine (1.0 g, 0.0072 mol), then 5-bromo-2,3-dihydro- 2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (2.15 g, 0.0072 mol) are added, and stirring is continued for 48 hours at room temperature. To the obtained solution hydrochloric acid in isopropanol (2.5 ml, 20 w/v %) is added and evaporated until dry in vacuum. The residual oily product is crystallized after standing for a few days. The crystals are mixed with ether, filtered, washed with ether. Thus, 3.0 g (87.7 %) of the title compound are obtained. The melting point of the product, crystallized from acetone is 126-127 C⁰. ^S

Example 72 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2-chloro- phenyl)-piperazin-l-yl]-propan-2-ol-hydrochloride

To the solution of ethanol (8 ml) under stirring at room temperature 4-(2-chloro- phenyl)~piperazine (0.98 g, 0.005 mol), then 5-bromo-2,3-dihydro-2,2-dimethyl- 7-(oxiranyl-methoxy)-benzofuran (1.5 g, 0.005 mol) are added, and stirring is continued for 28 hours at room temperature. The reaction mixture is evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (3.0 ml, 20 w/v %) and ether (10 ml) are added. The crystalline product is filtered, washed with ether. Thus 1.92 g (72.1 %) of the title compound are obtained. The melting point of the product, crystallized from ethyl acetate is 172- 176 C⁰.

Example 73 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3-chloro- phenyl)-piperazin-l-yl]-propan-2-ol

To the solution of sodium hydroxide (0.04 g, 0.001 mol) and water (16 ml) under stirring at room temperature 4-(3-chloro-phenyl)-piperazine (1.77 g, 0.009 mol), then 5-bromo-2,3-dihydro-2,2-dimethyl-7-(oxiranylmethoxy)-benzofuran (2.69 g, 0.009 mol) are added, and the reaction mixture is boiled for 3 hours. The reaction mixture is subject to decantation, the oily residue is dissolved in chloroform (15 ml, the solution is extracted with water (20 ml) and the aqueous phase is extracted with chloroform (15 ml). The united phases of chloroform are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The residual crystalline product is suspended with ether (10 ml), the product is filtered, washed with ether. Thus, 2.86 g (64.2 %) of the title compound are obtained. The melting point of the product, crystallized from acetonitrile is 135- 137 C⁰. S3

Example 74 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3-dihydro-7- chlom-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propan-2-ol-hydrochloride

To the solution of ethanol (8 ml) under stirring at room temperature 4-(2,3- dihydro-7-chloro-l,4-benzodioxan-5-yl)-piperazine (1.48 g, 0.0068 mol), then 5- bromo-2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (2.03 g, 0.0068 mol) are added, and stirring is continued for 72 hours at room temperature. The reaction mixture is evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (4 ml, 20 w/v%) and ether (10 ml) are added. The crystalline product is filtered, washed with ether. Thus, 2.38 g (59.3 %) of the title compound are obtained. The melting point of the product, crystallized from acetonitrile is 110-112 C⁰.

Example 75 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3- trifluoromethyl-phenyl)-piperazin-l-yl]-propan-2-ol-hydrochloride

To the solution of ethanol (8 ml) under stirring at room temperature 4-(3- trifluoromethyl-phenyl)-piperazine (1.15 g, 0.005 mol), then 5-bromo-2,3- dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (1.5 g, 0.005 mol) are added, and stirring is continued for 28 hours at room temperature. The reaction mixture is evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (3 ml, 20 w/v%) and ether (10 ml) are added. The crystalline product is filtered, washed with ether. Thus 2.81 g (99.3 %) of the title compound are obtained. The melting point of the product, crystallized from acetonitrile is 97.5-100.5 C⁰.

Example 76 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2-pyridyl)- piperazin-l-yl]-propan-2-ol-dihydrochloride CO

To the solution of ethanol (6 ml) under stirring at room temperature 4-(2- pyridyl)-piperazine (0.76 ml = 0.81 g, 0.005 mol), then 5-bromo-2,3-dihydro-2,2- dimethyl-7-(oxiranyl-methoxy)-benzofuran (1.5 g, 0.005 mol) are added, and stirring is continued for 24 hours at room temperature. The reaction mixture is evaporated until dry in vacuum, and the residual product is dissolved in dichloromethane (20 ml), and hydrochloric acid in isopropanol (4 ml, 20 w/v%) is added to the solution, then it is evaporated until dry in vacuum. The residue is suspended with ether (20 ml) and is put in refrigerator to obtain crystals. The crystalline product is filtered, washed with ether. Thus, 1.86 g (69.5 %) of the title compound are obtained. The melting point of the product, crystallized from methanol is 185-186 C⁰.

Example 77 l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4- (dibenzo/bJ7/l,4/thiazepin-7-yl)-piperazin-l-yl]-propan-2-ol-dihydrochloride- dihydrate

To the solution of ethanol (6 ml) under stirring at room temperature 4- (dibenzo/b,f//l,4/thiazepin-7-yl)-piperazine (1,70 g, 0.0058 mol), then 5-bromo- 2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran (1,73 g, 0.0058 mol) are added, and stirring is continued for 20 hours at room temperature. The reaction mixture is evaporated until dry in vacuum. To the residual oily product hydrochloric acid in isopropanol (6 ml, 20 w/v%) and ether (10 ml) are added. The crystalline product is filtered, washed with ether. Thus, 3.52 g (90.9 %) of the title compound are obtained. The residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of cyclohexane and ethyl acetate in different ratios. The suitable phases are evaporated 0.64 g (15.5 %) of the pure title compound are obtained. The melting point of the product, crystallized from acetonitrile is 158-162 C⁰. Example 78

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(3-trifluoromethyl-phenyl)-l,2,5,6-tetrahydro- pyridin-l-yl]-propoxy}-benzofuran-5-sulfonic acid amide

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid amide (1.66 g, 0.0052 mol), 4-(3-trifluoromethyl-phenyl)-l, 2,5,6- tetrahydro-pyridine hydrochloride (1.32 g, 0.005 mol) and anhydrous sodium carbonate (0.58 g, 0.0055 mol) under stirring is put in an oil bath warmed in advance to 160 C⁰ and is warmed at 150-160 C⁰ for 70 minutes. After cooling, the reaction mixture is divided between dichloromethane (10 ml) and water (10 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (10 ml). The united solutions of ethyl acetate water (10 ml) is added and the pH is adjusted to pH=4 with hydrochloric acid solution (10 w/w%). The phases are separated, and the pH of the aqueous phase is adjusted to pH=7 with sodium hydroxide solution (0.1 N) and extracted with ethyl acetate (2 x 20 ml). The united organic solvents are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus 1.12 g (43.7 %) of the title compound are obtained. The melting point of the product, crystallized from ethyl acetate is 128- 132 C⁰.

Example 79

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(5-fluoro-benzimidazole-l-yl)-piperidin-l-yl]- propoxy}-benzofuran-5-sulfonic acid amide

The mixture of 2,3-dmydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid amide (1.33 g, 0.004 mol), 4-(5-fluoro-benzimidazol-l-yl)- piperidine (0.96 g, 0.0044 mol) and anhydrous sodium carbonate (0.47 g, 0.0044 mol) under stirring is put in an oil bath warmed in advance to 160 C⁰ and is warmed at 150-160 C⁰ for 5 hours. After cooling, the reaction mixture is divided between dichloromethane (10 ml) and water (10ml) and the pH is adjusted to pH=2 with hydrochloric acid solution (10 w/w%). The phases are separated, and the organic phase is extracted with sodium hydroxide solution (10 ml, 0.1 N), with water (6 ml), then dried over anhydrous magnesium sulfate, and evaporated until dry in vacuum. The residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 0.7 g (32.4 %) of the title compound are obtained. Melting point: 94-98 C⁰.

Example 80

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(6-fluoro-benzimidazol-l-yl)-piperidin-l-yl]- propoxy}-benzofuran-5-sulfonic acid amide

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid amide (1.33 g, 0.004 mol), 4-(6-fluoro-benzimidazol-l-yl)- piperidine (1.05 g, 0.0048 mol) and anhydrous sodium carbonate (0.47 g, 0.0044 mol) under stirring is put in an oil bath warmed in advance to 140 C⁰ and is warmed for 4 hours at this temperature. After cooling, the reaction mixture is divided between dichloromethane (30 ml) and water (30 ml). The phases are separated, the organic phase evaporated until dry in vacuum. The residual product is dissolved in dichloromethane (20 ml), the solution is extracted with water (10 ml) and hydrochloric acid solution (2 ml, 10 w/w %), the aqueous phase is alkalized with sodium hydroxide solution (1 N) and is extracted with dichloromethane (2 x 20 ml). The united organic phase is extracted with water (10 ml), dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual product (0.94 g) is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 0.4 g (18.8 %) of the title compound are obtained. Melting point: 155-160 C⁰.

Example 81

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(5-chloro-benzimidazol-l-yl)-piperidin-l-yl]- propoxyj-benzofuran-S-sulfonic acid amide The mixture of 2,3-dihydro-2,2-dimemyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid amide (1,67 g, 0.005 mol), 4-(5-chloro-benzimidazol-l-yl)- piperidine (1,41 g, 0.006 mol) and anhydrous sodium carbonate (0.58 g, 0.0055 mol) under stirring is put in an oil bath warmed in advance to 180 C⁰ and is warmed at this temperature for 3 hours. After cooling, the reaction mixture is divided between ethyl acetate (15 ml) and water (15 ml), the pH is adjusted to pH=4 with hydrochloric acid solution (10 w/w%) and the phases are separated. The pH of the aqueous phase is adjusted to pH=8 with sodium hydroxide solution (1 N) and is extracted with the mixture of chloroform (2 x 20 ml) and methanol (10 ml). The united organic phase is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual title product (1,7 g, 63.8 %) is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 0.65 g (24.4 %) of the title compound are obtained. Melting point: 165-168 C⁰.

Example 82

2,3-Dihydro-2,2-dimethyl-7-β-[4~(3-chloro-phenyl)-piperazin-l-yl]-propoxy}- benzofuran-5-sulfonic acid amide

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-amide (0.96 g, 0.003 mol), 4-(3-chloro-phenyl)-piperazine (0.63 g, 0.0032 mol) and anhydrous sodium carbonate (0.38 g, 0.0036 mol) under stirring is put in an oil bath warmed in advance to 140 C⁰ and warmed at the same temperature for 2 hours. After cooling, the reaction mixture is divided between ethyl acetate (10 ml), water (10 ml) and hydrochloric acid solution (5 ml, 0.1 N), the phases are separated, the aqueous phase is extracted with ethyl acetate (10 ml). The united organic phase is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual title product (1.36 g, 94.4 %) is crystallized with ethyl acetate (15 ml). The precipitated product is filtered, washed with ethyl acetate. Yield 0.78 g (54.1 %) Melting point: 116-117 C⁰. Gk

Example 83

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(4-fluoro-phenyl)-piperazine-l-yl]-propoxy}- benzofuran-5-sulfonic acid amide

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-amide (1.60 g, 0.005 mol), 4-(4-fluoro-phenyl)-piperazine (1.08 g, 0.006 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) under stirring is put in an oil bath warmed in advance to 170 C⁰ and warmed at the same temperature for 1 hour. After cooling, to the crystallized reaction mixture ethyl acetate (20 ml) and water (10 ml) are added, and stirred for 1 hour, then filtered. Thus 1.96 g (84.5 %) of the title product are obtained. The melting point of the product, crystallized from isopropanol is 174-177 C⁰.

Example 84

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-l-yl]- propoxy}-benzofuran-5-sulfonic acid amide

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-amid (1.67 g, 0.005 mol), l-(2,3-dichloro-phenyl)-piperazine (1.27 g, 0.0055 mol) and anhydrous potassium carbonate (0.58 g, 0.0055 mol) under stirring is put in an oil bath warmed in advance to 160 C⁰ and warmed at the same temperature for 2 hours. After cooling to the reaction mixture ethyl acetate (20 ml), water (10 ml) and hydrochloric acid (5 ml, 10 w/v%) are added, the phases are separated, and the aqueous phase is extracted with ethyl acetate (20 ml). The united aqueous solvent is alkalized with sodium hydroxide solvent (1 N)₅ it is extracted with ethyl acetate (2 x 20 ml), and the united ethyl acetate solution is extracted with sodium hydroxide solution (10 ml, 1 N), divided and dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The 1.3 g (50.5 %) residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 1.08 g (42.0 %) of the title compound are obtained. Melting point: 153-156 C⁰.

Example 85

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(3-methoxy-phenyl)-piperazin-l-yl]-propoxy}- benzofuran-5-sulfonic acid amide

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid amide (1.60 g, 0.005 mol), l-(3-metoxy-phenyl)-piperazine (1.15 g, 0.0055 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) under stirring is put in an oil bath warmed in advance to 170 C⁰ and warmed at this temperature for 2 hours. After cooling, the reaction mixture is divided between ethyl acetate (10 ml) and water (10 ml), the phases are separated, the solution of ethyl acetate is dried over anhydrous magnesium sulfate, filtered and evaporated until dry in vacuum. The residual crystalline product is mixed with ethyl acetate (8 ml), filtered and washed with ethyl acetate. Thus 1.60 g (67.6 %) of the title compound are obtained. Melting point: 128-132 C⁰.

Example 86

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- propoxyj-benzofuran-5-sulfonic acid amide

2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5-sulfonic acid amide (0.96 g, 0.003 mol), l-(3-trifluoromethyl-phenyl)-piperazine (0.76 g, 0.0033 mol) and anhydrous sodium carbonate (0.35 g, 0.0033 mol) under stirring is put in an oil bath warmed in advance to 160 C⁰ and warmed at this temperature for 4 hours. After cooling, the reaction mixture is divided among ethyl acetate (20 ml) and water (20 ml) and hydrochloric acid (4 ml, 10 w/w %), the phases are separated, the solution of ethyl acetate is extracted with the mixture of water (6 ml) and sodium hydroxide solution (4 ml, 1 N), dried over anhydrous magnesium sulfate, filtered and evaporated until dry in vacuum. The residual 1,1 g product is subjected to chromatography on a column filled with Kieselgel 6OH using as GQ eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated, 0.56 g (36.3 %) of the title compound are obtained, which is crystallized with diisopropyl ether (10 ml). The precipitated crystals are filtered, washed with diisopropyl ether. Melting point: 118-121 C⁰.

Example 87

2,3-Dihydro-2,2-dimethyl-7-{3-[4-(2,3-dihydro-7-chloro-l,4-benzodioxan-5-yl)- piperazin-l-yl]-propoxy}-benzofuran-5-sulfonic acid amid hydrochloride

The mixture of 2,3-dmydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid amide (1.60 g, 0.005 mol), l-(2,3-dihydro-7-chloro-l,4- benzodioxan-5-yl)-piperazine (1.53 g, 0.006 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) under stirring is put in an oil bath warmed in advance to 140 C⁰ and warmed at this temperature for 1 hour. After cooling, the reaction mixture is divided between chloroform (20 ml) and water (10 ml), and hydrochloric acid solution (1 w/v%) is added, the phases are separated, the solution of chloroform is dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The residual 1.27 g oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable fractions are evaporated, the residue is dissolved in isopropanol (5 ml) and isopropanol (3 ml, 20 w/v %) is added to the solution. The precipitated crystals are filtered, washed with isopropanol. Thus 0.73 g (25.4 %) of the title compound are obtained. Melting point: 166-169 C⁰.

Example 88

2,3-Dihydro-2,2-dimethyl-7-β-[4-(l,2-benzi$othiazol-3-yl)-piperazin-l-yl]- propoxyj-benzofuran-5-sulfonic acid amide

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid amide (1,60 g, 0.005 mol), l-(l,2-benzisothiazol-3-yl)-piperazine (1.21 g, 0.0055 mol) and anhydrous sodium carbonate (0.58 g, 0.0055 mol) under stirring is put in an oil bath warmed in advance to 160 C⁰ and warmed at this temperature for 4.5 hours. After cooling the reaction mixture is divided between ethylacetate (20 ml) and water (15 ml), hydrochloric acid solution (7 ml, 10 w/v%) is added to the solution, the phases are separated, the aqueous phase is alkalized with sodium hydroxide solution (1 N), it is extracted with dichloromethane (20 ml), and solvent of dichloromethane is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual 2.0 g oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 1.0 g (39.8 %) of the title compound are obtained. Melting point: 186-191 C⁰.

Example 89 l-[(5-Sulfonamido-2,3-dihydw-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3- trifluoro-methyl-phenyl)-l,2,5,6-tetrahydro-pyridin-l-yl]-propan-2-ol

The mixture of 2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran-5- sulfonic acid-amide (1,80 g, 0.006 mol), 4-(3-trifluoro-methyl-phenyl)-l,2,5,6- tetrahydro-pyridine (1,66 g, 0.0063 mol) and anhydrous sodium carbonate (0.76 g, 0.0072 mol) under stirring is put in an oil bath warmed in advance to 160 C⁰ and warmed at this temperature for 3.5 hours. Then to the reaction mixture anhydrous sodium carbonate (0.76 g, 0.0072 mol) is added and the stirring is continued for 3.5 hours. After cooling the reaction mixture is divided between ethyl acetate (20 ml) and water (15 ml), then hydrochloric acid solution (16 ml, 0.1 N) is added to the solution, the phases are separated, the phase with ethyl acetate is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual 2.2 g oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 0.73 g (24.8 %) of the title compound are obtained. Melting point: 189-194 C⁰. Example 90 l-[(5-Sulfonamido-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3- chloro-phenyl)-piperazin-l-yl]-propan-2-ol

The mixture of 2,3-dihydro-2,2-diniethyl-7-(oxiranyl-methoxy)-benzofuran-5- sulfonic acid amide (1.80 g, 0.006 mol), 4-(3-chloro-phenyl)-piperazine (1.18 g, 0.006 mol) and anhydrous sodium carbonate (0.74 g, 0.007 mol) under stirring is put in an oil bath warmed in advance to 180 C⁰ and warmed at this temperature for 3 hours. After cooling to the a reaction mixture ethyl acetate (15 ml) and water (15 ml) are added, stirred for half an hour, then the precipitated product is filtered. The residual 2.1 g product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 1.5 g (50.4 %) of the title compound are obtained. The melting point of the product crystallized from acetonitrile is 203-207 C⁰.

Example 91 l-[(5-Sulfonamido-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(4- fluoro-phenyl)-piperazin-l-yl]-propan-2-ol

The mixture of 2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran-5- sulfonic acid amide (1.80 g, 0.006 mol), 4-(4-fluoro-phenyl)-piperazine (1.08 g, 0.006 mol) and anhydrous sodium carbonate (0.74 g, 0.007 mol) under stirring is put in an oil bath warmed in advance to 170 C⁰ and warmed at this temperature for 5 hours. After cooling to the a reaction mixture ethyl acetate (15 ml) and water (15 ml) are added, stirred for half an hour, then the precipitated product is filtered. The residual 1.8 g product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 1.3 g (45.2 %) of the title compound are obtained. Melting point: 215-218 C⁰. Example 92 l-[(5-Sulfonamido-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3- methoxy-phenyl)-piperazin-l-yl]-propan-2-ol

The mixture of 2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran-5- sulfonic acid amide (1.50 g, 0.005 mol), 4-(3-methoxy-phenyl)-piperazine (0.96 g, 0.86 ml, 0.005 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) under stirring is put in an oil bath warmed in advance to 180 C⁰ and warmed at this temperature for 4 hours. After cooling to the a reaction mixture ethyl acetate (20 ml) and water (25 ml) are added, stirred for half an hour, then the precipitated product is filtered. Thus 1.4 g, 56.9% of the title product are obtained. The melting point of the product crystallized from ethyl acetate is 162-166 C⁰.

Example 93 l-[(5-Sulfonamido-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-7-chloro-l_f4-benzodioxan-5-yl)-piperazin-l-yl]-propan-2-ol

The mixture of 2,3-dihydro-2,2-dimethyl-7-(oxiranyl-methoxy)-benzofuran-5- sulfonic acid amide (1.50 g, 0.005 mol), l-(2,3-dihydro-7-chloro-l,4- benzodioxan-5-yl)-piperazine (1.27 g, 0.005 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) is put under stirring in an oil bath warmed in advance to 200 C⁰ and warmed at this temperature for 2 hours. After cooling to the a reaction mixture ethyl acetate (20 ml) and water (30 ml) are added, the solution of ethyl acetate is dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus 1.3 g (46.9 %) of the title product are obtained. The melting point of the product, crystallized from acetonitrile is 194- 198 C⁰.

Example 94 l-{[(5-N-Methyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]-oxy}- 3-[4-(4-chloro-phenyl-amino)-piperidin-l-yl]-propane hydrochloride The mixture of 2,3-dihydro-2,2-dimemyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-N-methyl-amide (1.00 g, 0.003 mol), 4-(4-chloro-phenyl-amino)- piperidine (0.70 g, 0.0033 mol), triethylamine (10 ml) and JV-methyl-pyrrolidone (1,5 ml) is put under stirring in an oil bath warmed in advance to 120 C⁰ and kept at this temperature for 24 hours. After cooling the reaction mixture is divided between dichloromethane (20 ml) and water (15 ml), the phases are separated, to the phase of dichloromethane water (10 ml) is added, the pH of the mixture is adjusted to pH= 4 with hydrochloric acid (5 w/v%) and the phases are separated. The phase of dichloromethane water (10 ml) is added and the pH of the solution is adjusted to pH=9 with sodium hydroxide (1 N). The phases are separated, the organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated until dry in vacuum. The residual 2.1 g oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. By evaporating the suitable phases 0.70 g (42.8 %) of the title compound are obtained. Melting point: 130- 139 C⁰.

Example 95 l-{[(5-N-Methyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]-oxy}~

3-[4-(3-trifluoromethyl-phenyl-amino)-piperidin-l-yl]-propane

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-N-methyl amide (1.00 g, 0.003 mol), 4-(3-trifluoro-methyl-phenyl- amino)-piperidine (0.81 g, 0.0033 mol), triethylamine (10 ml) and iV-methyl- pyrrolidone (1.6 ml) is put under stirring in an oil bath warmed in advance to 120 C⁰ and warmed at this temperature for 10.5 hours. After cooling the reaction mixture is divided between dichloromethane (20 ml) and water (20 ml), the phases are separated, to the phase of dichloromethane water (10 ml) is added, the pH of the mixture is adjusted to pH= 3 with hydrochloric acid (5 w/v%) and the phases are separated. The phase of dichloromethane water (10 ml) is added and the pH of the solution is adjusted to pH=9 with sodium hydroxide (1 Ν). The phases are separated, the organic phase is dried over anhydrous magnesium ft sulfate, filtered, and evaporated until dry in vacuum. The residual 1.9 g oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 0.50 g (34.9 %) of the title compound are obtained. Melting point: 125-128 C⁰.

Example 96 l-{[(5-N-Methyl-$ulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]-oxy}-

3-[4-(6-chloro-benzimidazol-l-yl)-piperidin-l-yI]-propane

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-JV-methyl amide (1.34 g₅ 0.004 mol), 4-(6-chloro-benzimidazol-l- yl)-piperidine (0.85 g, 0.0044 mol) and anhydrous sodium carbonate (0.64 g, 0.005 mol) is put under stirring in an oil bath warmed in advance to 170 C⁰ and kept at this temperature for 6 hours. After cooling the reaction mixture is divided between dichloromethane (20 ml) and water (15 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate(10 ml), and the united solvent of ethyl acetate is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual 1.55 g oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated, the residue is mixed with diisopropyl ether and filtered. Thus 0.64 g (30.0 %) of the title compound are obtained. Melting point: 90-96 C⁰.

Example 97 l-{[(5-N-Methyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]-oxy}- 3-[4-(2,3~dihydro-2-oxo-5-trifluoro-methyl-benzintidazol-l-yl)-piperidin-l-yl]- propane hydrochloride

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-N-methyl-amide (0.93 g, 0.0028 mol), 4-(2,3-dihydro-2-oxo-5- trifluoro-methyl-benzimidazol-l-yl)-piperidine (0.86 g, 0.003 mol) and anhydrous sodium carbonate (0.35 g, 0.0033 mol) is put under stirring in an oil bath warmed in advance to 150 C⁰ and kept at this temperature for 2 hours. After cooling the reaction mixture is divided between ethyl acetate (15 ml) and water (10 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (15 ml), and the united solvent of ethyl acetate is extracted (2 x 10 ml) with hydrochloric acid solution (1 w/v %), is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual 0.9 g oily product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated, thus 0.43 g (24.8 %) of the title compound are obtained. Melting point: 145-148 C⁰.

Example 98 l-{[(5-N-Methyl-sulfonamido)~2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]-oxy}-

3-[4~(2,3-dihydro-5-chloro-2-oxo-benzitnidazol-l-yl)-piperidin-l-yl]-propane

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-iV-methyl-amide (1.00 g, 0.003 mol), 4-(2,3-dihydro-5-chloro-2- oxo-benzimidazol-l-yl)-piperidine (0.83 g, 0.0033 mol) and anhydrous sodium carbonate (0.38 g, 0.0036 mol) is put under stirring in an oil bath warmed in advance to 160 C⁰ and kept at this temperature for 2 hours. After cooling the reaction mixture is divided between ethyl acetate (20 ml) and water (20 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (15 ml), and the united solvent of ethyl acetate is extracted with hydrochloric acid solution ((2 x 10 ml, 1 w/v %). The precipitated product is a gluey oil, which is dissolved in dichloromethane (20 ml), the pH of the solution is adjusted to pH=6 with sodium hydroxide solution (1 N), the phases are separated, the organic phase is extracted with water(10 ml), dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. Thus 0.9 g foamy residue is obtained, which is crystallized with acetonitrile (10 ml). The crystals are filtered and washed with acetonitrile. Thus 0.5 g (30.4 %) of the title compound are obtained. Melting point: 200-205 C⁰. <?3

Example 99 l-{[(5-N~Methyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]-oxy}-

3-[4-(2,3-dihydro-6-chloro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propane

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-berizofuran-5- sulfonic acid-N-methyl-amide (1.00 g, 0.003 mol), 4-(2,3-dihydro-6-chloro-2- oxo-benzimidazol-l-yl)-piperidine (0.83 g, 0.0033 mol) and anhydrous sodium carbonate (0.38 g, 0.0036 mol) is put under stirring in an oil bath warmed in advance to 150 C⁰ and kept at this temperature for 4 hours. After cooling the reaction mixture is divided between ethyl acetate (15 ml) and water (10 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (5 ml), and the united solvent of ethyl acetate is extracted with hydrochloric acid solution (10 ml, 1 w/v %). The aqueous-hydrochloric acidic phase is acidified with sodium hydroxide solution (5 ml, 1 N), is extracted with dichloromethane (15 ml), the organic phase is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual 0.56 g product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of ethyl acetate and c-hexane in different ratios. The suitable phases are evaporated. 0.32 g (19.4 %) of the title compound are obtained. Melting point: 224-230 C⁰.

Example 100 l-{[(5-N-Methyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]-oxy}- 3-[4-(2.3-dihydro-7-chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane hydrochloride

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-iV-methyl-amide (0.90 g, 0.0027 mol), 4-(2.3-dihydro-7-chloro-l,4- benzodioxan-5-yl)-piperazine (0.71 g, 0.0028 mol) and anhydrous sodium carbonate (0.35 g, 0.003 mol) is put under stirring in an oil bath warmed in advance to 145 C⁰ and warmed at this temperature for 4 hours. After cooling the reaction mixture is divided between ethyl acetate (15 ml) and water (10 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (10 ml), and the united solvent of ethyl acetate is extracted with hydrochloric acid solution (2 x 10 ml, 1 w/v%). The precipitated crystalline product from the aqueous phase is filtered, and washed with water. Thus 0.66 g (41,5 %) of the title compound are obtained. The product is mixed with ethyl acetate and filtered. Melting point: 134-137 C⁰.

Example 101 l-{[(5-N-methyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-henzofuran-7-yl]-oxy}- 3-[4-(3-trifluoro-methyl-phenyl)-l,2,5,6-tetrahydro-pyridin-l-yl]-propane hydrochloride

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-iV-methyl amide (0.50 g, 0.0015 mol), 4-(3-trifluoro-methyl- phenyl)-l,2,5,6-tetrahydro-pyridine (0.45 g, 0.0017 mol) and anhydrous sodium carbonate (0.32 g, 0.003 mol) is put under stirring in an oil bath warmed in advance to 150 C⁰ and kept at this temperature for 3 hours. After cooling the reaction mixture is divided between ethyl acetate (10 ml) and water (5 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (10 ml), hydrochloric acid solution (1 w/v %), with water (5 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The residual 0.61 g oil is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 0.22 g (26.1 %) of the title compound are obtained. The product is mixed with ethyl acetate and filtered. Melting point: 124-127 C⁰.

Example 102 l-{[(5-N-isopropyl-sulfonamido)-2_f3-dihydro-2,2-dimethyl-benzqfuran-7-ylJ- oxy}-3-[4-(2,3-dihydro-6-chloro-2-oxo-benzinιidazol-l-yl)-piperidin-l-yl]- propane ψs

The mixture of 2,3-dihydro-2,2-dimemyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-iV-izopropyl-amide (1.09 g, 0.003 mol), 4-(2,3-dihydro-6-chloro-2- oxo-benzimidazole-l-yl)-piperidine (1.01 g, 0.004 mol), triethylamine (10 ml) and iV-methyl-pirrolidone (3 ml) is put under stirring in an oil bath warmed in advance to 130 C⁰ and kept at this temperature for 26 hours. After cooling the reaction mixture is evaporated until dry in vacuum, the residue is divided among water (15 ml), hydrochloric acid (15 ml, 0.1 N) and dichloromethane (30 ml), the phases are separated, the solvent of dichloromethane is dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The 3.2 g residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated, thus 0.80 g (46.2 %) of the title compound are obtained. The product is mixed with ethyl acetate and filtered. Melting point: 196-200 C⁰.

Example 103 l-{[(5~N-Isopropyl-$ulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]- oxy}-3-[4-(3-trifluoro-methyl-phenyl)-l,2,5,6-tetrahydro-pyridin-l-yl]-propane

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-N-isopropyl-amide (0.94 g, 0.0026 mol), 4-(3-trifluoro-methyl- phenyl)-l,2,5,6-tetrahydro-pyridine (0.61 g, 0.0027 mol) and anhydrous sodium carbonate (0.55 g, 0.0052 mol) is put under stirring in an oil bath warmed in advance to 135 C⁰ and kept at this temperature for 5 hours. After cooling the reaction mixture is divided between ethyl acetate (15 ml) and water (10 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (10 ml), the united phases of ethyl acetate are extracted with hydrochloric acid solution (2 x 10 ml, 1 w/v %), dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The residual 1.3 g oil is dissolved in dichloromethane (15 ml), extracted with sodium hydroxide (20 ml, 1 N), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. U

Thus 1.1 g oily base are obtained. The residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated, thus 0.6 g (41.7 %) of the title compound are obtained. The product is mixed with diisopropyl ether and filtered. Melting point: 115-118 C⁰.

Example 104 l-{[(5-N-Isopropyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]- oxy}-3-[4-(2.3-dihydro-7-chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane hydrochloride

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-JV-izopropyl amide (0.87 g, 0.0024 mol), 4-(2,3-dihydro-7-chloro- l,4-benzodioxane-5-yl)-piperazine (0.64 g, 0.0025 mol) and anhydrous sodium carbonate (0.31 g , 0.0029 mol) is put under stirring in an oil bath warmed in advance to 130 C⁰ and kept at this temperature for 7 hours. After cooling the reaction mixture is divided between ethyl acetate (15 ml) and water (15 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (15 ml), the united phases of ethyl acetate are extracted with hydrochloric acid solution (2 x 10 ml, 1 w/v %), dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. To the residual product sodium hydroxide solution (5 ml, 1 N), water (10 ml) and dichloromethane (10 ml), the phases are separated, the aqueous phase is extracted with dichloromethane (10 ml), the solutions of dichloromethane are united, dried over anhydrous magnesium sulfate, filtered and evaporated until dry in vacuum. Thus 1.27 g oily product are obtained. The residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated, thus 0.53 g (35.8 %) of the title base are obtained, which is dissolved in ethyl acetate, then hydrochloric acid solution (10 w/w%) is added to the mixture. The precipitated crystals are filtered. Thus, 0.5 g of the title compound are obtained. Melting point:135-139 C⁰. ¹Pf

Example 105 l-{[(5-N-Cyclopropyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]- oxy}-3-[4-(3-trifluoro-methyl-phenyl)-l,2,5,6-tetrahydro-pyridin-l-yl]-propane hydrochloride

The mixture of 2,3-dihydro-2,2-dimemyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-N-cyclopropyl-amide (1.08 g, 0.003 mol), 4-(3-trifluoro-methyl- phenyl)-l,2,5,6-tetrahydro-pyridine (0.75 g, 0.0033 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) is put under stirring in an oil bath warmed in advance to 140 C⁰ and kept at this temperature for 5 hours. After cooling the reaction mixture is divided between ethyl acetate (20 ml) and water (20 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (10 ml), the united phases of ethyl acetate are extracted with hydrochloric acid solution (2 x 10 ml, 1 w/v %), dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The 1.6 g residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated, thus 0.82 g (46.5 %) of the title compound are obtained. The product is mixed with diisopropyl ether and filtered. Melting point: 90-100 C⁰.

Example 106 l-{[(5-N-Cyclopropyl-sulfonamido)-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl]- oxy}-3-[4-(2.3-dihydro-7-chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-iV-cyclopropyl-amide (1,08 g, 0.003 mol), 4-(2.3-dihydro-7-chloro- l,4-benzodioxan-5-yl)-piperazine (0.84 g, 0.0033 mol) and anhydrous sodium carbonate (0.64 g, 0.006 mol) is put under stirring in an oil bath warmed in advance to 120 C⁰ and kept at this temperature for 6 hours. After cooling the reaction mixture is divided between ethyl acetate (40 ml) and water (20 ml), the phases are separated, the aqueous phase is extracted with ethyl acetate (10 ml), the united phase of ethyl acetate is extracted with hydrochloric acid solution (2 x 10 ml, 1 w/v%), dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. To the residusal product sodium hyroxide solution (5 ml, 1 N), water (10 ml) and dichloromethane (10 ml) are added, the phases are separated, the aqueous solution is extracted with dichloromethane (10 ml). The solvents of dichloromethane is united, dried over anhydrous magnesium sulfate, filtered, and evaporated until dry in vacuum. The 1.5 g residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and n-hexane in different ratios. The suitable phases are evaporated 1.2 g (69.1 %) of the title compound are obtained. The product is mixed with diisopropyl ether and filtered. Melting point: 143-145 C⁰.

Example 107 l-{[(5-N-(3,4-Dichlorophenyl-sulfonamido)-2,3-dihydro-2,2-dimethyl- benzofuran-7-yl]-oxy}-3-[4-(2-methoxy-5-trifluoro-methyl-phenyl)~piperazin-l- yl]-propane hydrochloride

The mixture of 2,3-dihydro-2,2-dimethyl-7-(3-chloro-propoxy)-benzofuran-5- sulfonic acid-N-(3,4-dichlorophenyl)-amide (2.32 g, 0.005 mol), l-(2-methoxy-5- trifluoro-methyl-phenyl)-piperazine-hydrochloride (1,56 g, 0.0055 mol) and anhydrous sodium carbonate (1.06 g, 0.01 mol) is put under stirring in an oil bath warmed in advance to 130 C⁰ and kept at this temperature for 6 hours. After cooling the reaction mixture is divided between ethyl acetate (15 ml) and water (10 ml), the phases are separated, the phase of ethyl acetate is extracted with hydrochloric acid solution (2 x 10 ml, 1 w/v %), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The 4.2 g residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and methanol in different ratios. The suitable phases are evaporated, thus 1.5 g (33.6 %) of the title compound are obtained. Melting point: 136-14O C⁰. ¥3

Example 108 l-{[(5-N-(3,4-Dichlorophenyl-sulfonamido)-2,3-dihydro-2,2-dimethyl- benzofuran-7-yl]-oxy}-2-[4-(2-methoxy-5-trifluoro-methyl-phenyl)-piperazin-l- ylj-ethane

The mixture of 2,3-dihydro-2,2-dimemyl-7-(2-chloro-ethoxy)-benzofuran-5- sulfonic acid-iV-(3,4-dichlorophenyl)-amide (0.90 g, 0.002 mol), l-(2-methoxy-5- trifluoro-methyl-phenyl)-piperazine hydrochloride (1,62 g, 0.0022 mol) and anhydrous sodium carbonate (0.42 g, 0.004 mol) is put under stirring in an oil bath warmed in advance to 150 C⁰ and kept at this temperature for 3 hours. After cooling the reaction mixture is divided between ethyl acetate (15 ml) and water (15 ml), the pH of the phase of ethyl acetate is adjusted to pH=6 with hydrochloric acid solution (5 ml 1 w/v%), the phases are separated, the organic phase dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. The 1,17 g residual product is subjected to chromatography on a column filled with Kieselgel 6OH using as eluent a mixture of dichloromethane and petroleum ether in different ratios. The suitable phases are evaporated, thus 0.66 g (48.9 %) of the title compound are obtained. Melting point: 154- 158 C⁰.

Example 109

1-([(5-N-(IR-1 ,7.7-trimethyl-bicyclo[2.1.1]hept-2-yl-sulfonamido)-2,3-dihydro-

2,2-dimethyl-benzofuran-7-yl]-oxy}-2-[4-(2-methoxy-5-trifluoro-methyl- phenyl)-piperazin-l-yl]-ethane

The mixture of 1.11 g (0.0025 mol) 2,3-dihydro-2,2-dimethyl-7-(2-chloro- ethoxy)-benzofuran-5-sulfonic acid-iV-( IR-1 ,7.7-trimethyl-biciklo [2.1.1 ]hept-2- yl)-amid, 0.74 g (0.003 mol) 4-(2-methoxy-5-trifluoro-methyl-phenyl)-piperazin and 0.64 g (0.006 mol) anhydrous sodium carbonate is put under stirring in an oil bath warmed in advance to 150 C⁰ and kept at this temperature for 4 hours. After cooling the reaction mixture is divided between ethyl acetate (20 ml) and water (20 ml), the phases are separated, the aqueous phase is extracted with water (20 ml), dried over anhydrous sodium sulfate, filtered, and evaporated until dry in So vacuum. To the residual oily product ethyl acetate (5 ml) is added and the crystallized product is filtered. Thus 0.77 g (46.2 %) of the title compound are obtained. Melting point: 96-103 C⁰.

Claims

UClaims

1. Selective 5HT₇ receptor binding benzofuran derivatives of general formula Q₅

(I) wherein X represents a halogen atom or

SO₂NR¹R² group, wherein

Q together with groups A and B represents a thiophene ring and their pharmaceutically suitable acid addition salts, with the proviso that if Y represents 2-hydroxy propylene group, A represents a carbon atom, B represents CH group, and Q represents 3-trifluoro-methyl-phenyl group, then X does not represent bromo atom.

2. Selective 5HT₇ receptor binding benzofuran derivatives of general formula (I),

(I) wherein X represent chloro atom or bromo atom or

SO₂NR¹R² group, wherein

R¹ and R² represent, independently, a hydrogen atom, C_1-3 alkyl group, phenyl group substituted with one or two chloro atom or bromo atom or

1 ,7.7-trimethyl-bicyclo[2,2, 1 ]hept-2-yl group,

Y represents C_2-4 alkylene group, optionally substituted with hydroxy group, A represents carbon atom, nitrogen atom or CH group, B represents CH- or CH₂-group, Q represents methyl group; or phenyl group optionally substituted with one or two chloro atoms or fluoro atom, methoxy group or trifluoromethyl group; phenylamino group optionally substituted with chloro atom or trifluoromethyl group; pyridine heterocycle; benzisoxazole or benzisothiazole heterocycle, optionally substituted with a fluoro atom; benzimidazole or benzimidazolone heterocycle, optionally substituted with chloro atom, fluoro atom, trifluoromethyl-group on the benzene ring, or substituted with a methyl group on a nitrogen atom; benzodioxane heterocycle, optionally substituted with a chloro atom on the benzene ring; pyridazinone heterocycle substituted with a chloro atom; dibenzothiazepine heterocycle or

3. l-(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-2-oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl] -propane, l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzoturan-7-yl)-oxy]-3-[4-(2,3- dihydro-5-fluoro-2-oxo-benzimidazol- 1 -yl)-piperidin- 1 -yl] -propane hydrochloride, l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-5-chloro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propane, l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-7-chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane, l-[(2,3-Dihydro-2,2-dimethyl-5-chloro-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-5-fluoro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol, l-[(5-Bromo-2,3-dihydiO-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(4- chloro-phenyl)-piperazin- 1 -yl] -propane,

1 - [(5-Bromo-2,3 -dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy] -3 -[4-(2,3 - dihydro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propane-hydrochloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-5-fluoro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2₅3- dihydro-7-chloro-l,4-benzodioxan-5-yl)-piperazin-l-yl]-propane-dihydro- chloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[(2,3- dihydro-7-chloro- 1 ,4-benzodioxan-5-yl)-piperazin- 1 -yl]-butane-dihydro- chloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-4-[4-(6- fluoro-benzisoxazol-3-yl)-piperidin-l-yl]-butane, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(2,3- dihydro-2-oxo-benzimidazol-l-yl)-piperidin-l-yl]-propan-2-ol-hydro- chloride, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(6- fluoro-benzisoxazol-3 -yl)-piperidin- 1 -yl] -propan-2-ol, l-[(5-Bromo-2,3-dihydro-2,2-dimethyl-benzofuran-7-yl)-oxy]-3-[4-(3- chloro-phenyl)-piperazin- 1 -yl] -propan-2-ol,

1 - { [(5 -N-isopropyl-sulfonamido)-2,3 -dihydro-2,2-dimethyl-benzofuran-7- yl]-oxy } -3 - [4-(2,3 -dillydro-6-chloro-2-oxo-benzimidazol- 1 -yl)-piperidin- 1 - yl] -propane and pharmaceutically suitable acid additional salts thereof.

4. Process for the preparation of selective 5HT₇ receptor binding benzofuran derivatives of general formula (I) and pharmaceutically suitable acid additional salts thereof, characterized in that a. when in the general formula (I)

(I)

Y represents C_2-6 alkylene group, X, A, B and Q represent as defined in Claims 1 and 2 then a halide of general formula (II), $_>5

wherein X represents as defined in claims 1 and 2, Y represents C_2-6 alkylene group, Hal represents a halogen atom, is reacted with a secondary amine of general formula (IV)₅

-B

HN A-Q

(IV)

wherein A, B and Q represent as defined in Claims 1 and 2, or b. when in the general formula (I)

(D

Y represents C_2-6 alkylene group substituted with a hydroxyl group, X, A, B and Q represent as defined in Claims 1 and 2 then an epoxide of a general formula (III),

(in) wherein X represent as defined in Claims 1 and 2 is reacted with a secondary amine of general formula (IV),

(IV) wherein A, B and Q represent as defined in Claims 1 and 2 and if desired an obtained base of the general formula (I) is reacted with an inorganic or organic acid to form a pharmaceutically suitable acid additional salt thereof, or it is liberated from the acid addition salt with a base.

5. Halide compounds of general formula (II)

wherein X represents a halogen atom or SO₂NR¹R² group, wherein R^!and R² represent as defined in Claims 1 and 2, Y represents C_2-6 alkylene group, Hal represents a halogen atom, with the proviso that if Y represents propylene- group, Hal represents bromo atom, then X does not represent bromo atom.

6. A compound of general formula (II),

(HI) wherein X represents as defined in Claims 1 and 2, with the proviso that X does not represent bromo atom. 8£

7. Compounds of general formula (IX)

and (X)

8. Compounds of general formula (XII),

wherein R and R represent as defined in Claims 1 and 2 for the general formula (I).

9. A pharmaceutical composition comprising as active ingredient a therapeutically effective dose of one or more compounds of general formula (I) as defined in Claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof and one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

10. Use of a pharmaceutical composition according to Claim 9 for the treatment and prevention of 5HT₇ receptor relating disorders of the central nervous system and/or cardiovascular disorders. SS

11. Use of one or more compounds of general formula (I) as defined in Claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof, in the manufacture of a medicament for the prevention and/or treatment of 5HT₇ receptor relating disorders of the central nervous system and/or cardiovascular disorders.

12. Method of treatment characterized that administering for a patient suffering from 5HT₇ receptor relating disorders, especially disorders of the central nervous system and/or cardiovascular disorders a non-toxic dose of one or more compounds of general formula (I) as defined in Claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof.