SK1352000A3 - 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives interacting with the dopamine d4 receptor - Google Patents

Abstract

2(4-Aryl or Heteroaryl-piperazin-1-ylmethyl)-1H-Indole derivatives of formula (I) wherein a, T, V, X, Y, Z, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are as defined above, their pharmaceutically acceptable salts and pharmaceutical compositions containing such compounds or their salts interacting with the dopamin D4 receptor.

Description

2- (4-aryl or heteroarylpiperazin-1-ylmethyl) -1H-indole derivatives

Field of the invention

The present invention relates to 2- (4-aryl or heteroarylpiperazin-1-ylmethyl) -1H-indole derivatives having central dopaminergic activity. Such compounds are useful in the treatment of central nervous system (CNS) disorders. The invention also relates to a method of using these compounds in the treatment of the above disorders in mammals, particularly humans, and suitable pharmaceutical compositions.

It is well known that dopamine receptors appear to be useful for many animal body functions. For example, altered functions of these receptors participate in the genesis of psychosis, drug addiction, compulsive disorders, bipolar disorders, vision, vomiting, sleep, nutrition, learning, memory, sexual behavior, regulation of immunological responses and blood pressure. Since these receptors control a large number of pharmacological events, all of which are not yet known, it is possible that compounds acting primarily on the D4 dopamine receptor may exhibit a wide range of therapeutic effects in humans.

The 2- (4-aryl or heteroarylpiperazin-1-ylmethyl) ind-indole derivatives of this invention, including tautomers, enantiomers, and acceptable acid addition salts, are centrally acting D4 dopamine receptor agonists and are thus useful for enhancing consciousness and treating CNS diseases such as is Parkinson's disease, Alzheimer's disease, learning and memory abnormalities.

Another feature of the present invention is the use of combinations of the compounds of the present invention in conjunction with D1, D2, D3 or D5 dopamine receptor agonists such as L-dopa and D2 agonists in the treatment of CNS diseases such as Parkinson's disease, Alzheimer's, attention deficit and learning disorders. memory abnormalities.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein the dashed line represents an optional double bond, and is 0 or 1, wherein when a is 0, X may form an optional double bond with the carbon attached to V,

V is CHR ¹⁰ , wherein R ¹⁰ is hydrogen or (C 1 -C 8) alkyl,

T is nitrogen or CH,

X is nitrogen or CR ¹¹ where R ¹¹ is hydrogen, (C 1 -C 8) alkyl, ( ^C 1 -C 8) alkoxy, hydroxy or cyano,

Y and Z are each independently nitrogen or CR ¹² , wherein R ¹² is hydrogen, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 6) alkoxy or (C 1 -C 6) alkyl,

R ¹ is hydrogen, fluoro, chorus, bromo, trifluoromethyl, trifluoromethoxy, cyano or (C _x -C) alkyl,

R ² , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen, fluorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 8) alkoxy and (C 1 -C 8) alkyl,

R ³ and R ⁴ are each independently hydrogen or (C 1 -C 6) alkyl, and

R ⁵ is hydrogen, (C 1 -C 6) alkoxy, trifluoromethyl, cyano, (C 1 -C 6) alkyl or R ¹³ CO-, wherein R ¹³ is amino, (C 1 -C 6) alkylamino, ((C 1 -C 6) alkyl) ₂ amino , (C ₁ -C 8) alkyl, (C 1 -C 8) aryl, or when a is 1, R ¹ and R ¹⁰ may be taken together with the carbons to which they are attached to form a compound of formula II

where broken lines represent possible bonds,

T, X, Y, Z, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above, b is 0 or 1, and

A and B are each independently CH, CH ₂ , oxygen, sulfur, NH or nitrogen, with the proviso that when X is nitrogen, the optional double bond between X and V does not exist, provided that when b is 0, the optional double bond between A and B do not exist, and with the proviso that when b is 1, A and B cannot both be oxygen or sulfur.

The term alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon groups having unbranched, branched or cyclic moieties or combinations thereof.

The term alkoxy, as used herein, includes O-alkyl groups wherein alkyl is as defined above.

The term treatment as used herein refers to reversing, ameliorating or inhibiting the development or prevention of a disorder or condition to which it refers, or one or more symptoms of such disorders or conditions. The term treatment as used herein refers to the treatment effect as defined immediately above.

The term disorders of the dopamine system as used herein refers to disorders whose treatment may be affected or alleviated by a change (i.e., increase or decrease) of dopamine-mediated neurotransmission.

The compounds of the invention as ligands for dopamine receptor subtypes, in particular dopamine D4 receptor in the body, are accordingly used in the treatment of disorders of the dopamine system.

The compounds of formula I may have chiral centers and therefore exist in different enantiomeric forms. The present invention relates to all optical isomers and stereoisomers of these compounds of Formula I and mixtures thereof.

Preferred compounds of formula I include those wherein X is nitrogen.

Other preferred compounds of formula I include those wherein Y and Z are each CR ¹² , wherein R ¹² is hydrogen or fluoro.

Other preferred compounds of formula I include those wherein R ² is hydrogen, fluoro or chloro.

Other preferred compounds of formula I include those wherein R ^3, R ⁴ and R ⁵ are hydrogen.

Other preferred compounds of formula I include those wherein R ⁷ is fluoro or chloro.

Other preferred compounds of formula I include those wherein R ⁹ is fluoro, chloro, bromo or alkoxy.

More preferred compounds of formula I include compounds wherein X is nitrogen, Y and Z are each CR ¹³ , wherein R ¹³ is hydrogen or fluoro, R ² is hydrogen, fluoro or chloro, R ³ , R ⁴ and R ⁵ are hydrogen, R ⁷ is fluoro or chloro and R ⁹ is fluoro, chloro, bromo or alkoxy.

I

Particularly preferred compounds of formula I include the following compounds:

- [4- (3-trifluoromethylphenyl) piperazin-l-ylmethyl] indole--ΙΗ,

5-fluoro-2- [4- (3-trifluoromethylphenyl) piperazin-l-ylmethyl] indole-ΙΗ,

5-fluoro-2- [4- (4-fluorophenyl) piperazin-l-ylmethyl] indole--ΙΗ,

5-fluoro-2- [4- (4-fluorophenyl) piperazin-l-ylmethyl] indole--ΙΗ,

5-fluoro-2- (4-pyridin-2-yl-piperazin-l-ylmethyl) indole--ΙΗ,

2- [4- (6-chloropyridazine-3-yl) piperazin-l-ylmethyl] -5-fluórΙΗ-indole,

5-fluoro-2- (4-5'-fluoro] pyridin-2-ylpiperazin-1-ylmethyl) 1H-indole,

2- (4-pyridin-2-yl-piperazin-l-ylmethyl) -ΙΗ-azaindole,

5-fluoro-2- (4-pyridin-2-ylpiperazin-1-ylmethyl) -ΙΗ-azaindole; and

2 - [- (4-fluorophenyl) piperazin-l-ylmethyl] -H-azaindole.

The present invention also relates to a method of treating disorders of the dopamine system including psychotic disorders (affective psychosis, schizophrenia and schizoaffective disorders), locomotor disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, Hunting Disease, Parkinson's Disorder, Tardive Dystonia) diseases), gastrointestinal disorders (gastric acid secretion or vomiting), chemical abuse, chemical dependence, substance abuse, vascular or cardiovascular disorders, (massive heart failure and hypertension), ocular disorders, and sleep disorders in mammalian species, including mammalian species, 4 a dopamine receptor according to Formula I, or a pharmaceutically acceptable salt thereof, which is effective in treating such a disorder.

The present invention also relates to a method of treating disorders of the dopamine system including psychotic disorders (affective psychosis, schizophrenia and schizoaffective disorders), locomotor disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Parkinson's disease, Gilles deinson's disease, Gilles deinson's disease) or Huntington's disease), gastrointestinal disorders (gastric acid secretion or vomiting), chemical abuse, chemical dependence, substance abuse, vascular and cardiovascular disorders (massive heart failure and hypertension), ocular disorders and sleep disorders, including cervical disorders, A D4 dopamine receptor according to Formula I or a pharmaceutically acceptable salt thereof, in association with one or more dopamine receptor D1, D2, D3 or D5 agonists, which is in the treatment of such a disorder.

The present invention also relates to pharmaceutical compositions for the treatment of dopamine system disorders including psychotic disorders (affective psychosis, schizophrenia and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles de la Tourinson's disease, Gilles de la Tourinson's disease or Huntington's disease), gastrointestinal disorders (gastric acid secretion or vomiting), chemical abuse, chemical dependence, substance abuse, vascular and cardiovascular disorders (massive heart failure and hypertension), ocular disorders and sleep disorders in mammals, including administering to a mammal a compound of the mammal. The D4 dopamine receptor of Formula I, or a pharmaceutically acceptable salt thereof, which is effective in treating such a disorder.

The present invention also relates to a pharmaceutical composition for the treatment of dopamine system disorders including psychotic disorders (affective psychosis, schizophrenia and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles de la Tourinson's disease, Gilles de la Tourinson's disease or Huntington's disease), gastrointestinal disorders (gastric acid secretion or vomiting), chemical abuse, chemical dependence, substance abuse, vascular and cardiovascular disorders (massive heart failure and hypertension), ocular disorders and sleep disorders in mammals, including administering to a mammal a compound of the mammal. The D4 dopamine receptor of Formula I, or a pharmaceutically acceptable salt thereof, in association with one or more dopamine receptor D1, D2, D3 or D5 agonists which is effective in the treatment of such a disorder.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction schemes illustrate the preparation of the compounds of this invention. Unless otherwise indicated, α, T, V, X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ # R ⁶ , R ⁷ , R ⁸ and R ⁹ in these reaction schemes and discussion which follows is as defined above.

Scheme 1

(I)

Scheme 2

(I)

In reaction 1 of Scheme 1, compounds of formula III and IV are combined to form the corresponding compound of formula I by first treating compound III with O-, N-dimethylhydroxylamine hydrochloride, bicyclohexylcarbodiimide and a base such as triethylamine in a polar aprotic solvent such as methylene chloride. The hydroxamide intermediate thus formed is reduced using a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran.

Reductive amination of the aldehyde intermediate thus formed is carried out by reacting the aldehyde with a compound of formula IV in the presence of sodium triacetoxyborohydride and a polar solvent such as dichloroethane. The reaction mixture is stirred under an inert atmosphere at room temperature for between about 40 hours to about 56 hours, preferably about 48 hours.

In reaction 1 of Scheme 2, compounds of formula VI wherein L is a leaving group such as chlorine, bromine, methoxy or any activated ester derivative such as paranitrophenyl ester, hydroxybenzotriazolester, N-hydroxysuccinimide ester or hydroxy and compound of formula IV is combined to form the corresponding methanone compound of formula III by reaction of compounds VI and IV in the presence of diisopropylethylamine, cabodiimide or dehydrating agent and a polar aprotic solvent such as methylene chloride or in the form of mixtures containing, if necessary, combinations of organic solvents or water such as combinations of cyclic and acyclic mono and dialkylamides; and "C ₄₎ alcohols, halogenated solvents, or acyclic and cyclic alkylethers at temperatures between about 0 ^and C to about 150 ° C, preferably about 0C and the boiling point of the solvent mixture. The addition of an acid acceptor such as an alkyl carbonate, a tertiary amine, or a similar reagent may be useful.

In reaction 2 of Scheme 2, the methanone compound of formula V is converted to the corresponding compound of formula I wherein R ³ and R 6 are hydrogen by reducing compound V with a reducing agent such as lithium aluminum hydride or borane derivative in the presence of a polar aprotic solvent such as tetrahydrofuran. about 10 hours to about 14 hours, preferably about 12 hours.

For each of the above reactions, the pressure is not critical.

Pressures in the range of about 0.5 atm to about 3 atm are suitable and ambient pressure (generally about 1 atm) is preferred for its convenience.

Also, for these reactions, where the preferred temperature varies according to the respective reacted compounds, no preferred temperature is determined. For such reactions, temperatures for the appropriate reactants determined by monitoring the reaction using thin layer chromatography may be preferred.

The novel compounds of formula I and their pharmaceutically acceptable salts (referred to herein as the therapeutic compounds of the invention) are useful as dopaminergic agents, i.e., they have the ability to alter dopamine-mediated neurotransmissions in mammals, including humans. They are also capable of acting as therapeutic agents in the treatment of a variety of conditions in a mammal whose treatment or prevention can be accomplished or alleviated by increasing or decreasing dopamine-mediated neurotransmission.

The compounds of formula I are basic in nature and are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to first isolate a compound of Formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the salt back to the free base by treatment with an alkaline reagent and subsequently converting the free base into a pharmaceutically acceptable acid addition salt.

The acid addition salts of these basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol.

Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salts may be prepared from a solution of the free base in an organic solvent by adding a suitable mineral or organic acid to the solution.

The therapeutic compounds of the invention may be administered orally, transdermally (e.g., using a patch), parenterally, or topically.

Oral administration is preferred. Generally, the compounds are preferably administered in doses ranging from about 0.1 mg to about 1000 mg per day or 1 mg to 1000 mg per day in some cases, although variations may occur depending on the weight and condition of the person is treated and the appropriate route of administration selected. In some cases, dosing levels below the lower limit of the above range may be adequate, while in other cases even larger dosages may be used without causing any adverse side effect, provided that such larger dosages are first divided into a few small dosages for daytime administration. .

The therapeutic compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes set forth above, and such administration may be in one or more doses. The novel therapeutic compounds of the invention may optionally be formulated in a wide variety of different dosage forms, i. They may be combined with various pharmaceutically acceptable carriers in the form of tablets, capsules, troches, lozenges, pills, hard candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, rinses, ointments, elixirs, syrups and the like.

Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, by way of example. In addition, the oral pharmaceutical compositions may be suitably sweetened and / or flavored.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, disodium phosphate and glycine may be used together with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates together with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia.

In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talk are suitable for tableting purposes, which are often very useful. Solid compositions of a similar type may also be employed as fillers in gelatin capsules, preferred agents in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.

When aqueous suspensions and / or elixirs for oral administration are desired, the active ingredient may be combined with various sweeteners or flavor enhancers, coloring agents or coloring agents and, if necessary, emulsifying and / or suspending agents as well as together with such diluents as water , ethanol, propylene glycol, glycerin and various similar combinations thereof.

For parenteral administration, solutions of the present invention in either sesame or peanut oil or in aqueous propylene glycol can be used. The aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

Furthermore, it is possible to administer the compounds of the present invention topically while treating inflammatory conditions of the skin and this can preferably be done with creams, jellies, jellies, pastes, ointments and the like according to standard pharmaceutical practice.

The ability of the compounds to bind to mammalian dopamine receptors and the relative ability of the compounds of the invention to inhibit [ ³ H] -spiperone binding to human dopamine D4 receptor subtypes expressed in clonal cell lines was measured using the following procedure.

D4 receptor binding capacity

Determination of D4 receptor binding ability has been described by Van Tol et al. (Nature, 1991, 350, 610). Clonal cell lines expressing the human dopamine D4 receptor are obtained and homogenized (polytron) in 50 mM tris: HCl (pH 7.4 at 4 ° C) buffer containing 5 mM EDTA, 1.5 mM calcium chloride (CaCl ₂ ), 5 mM magnesium chloride (MgCl ₂ ), 5 mM potassium chloride (KCl) and 120 mM sodium chloride (NaCl).

The homogenates are centrifuged for 10-15 minutes at 48,000 g and the resulting pellets are resuspended in buffer at a concentration of 150-250 mg / ml. For saturation experiments, 0.75 ml aliquots are incubated in tissue homogenate in triplicate with increasing concentrations of [ ³ H] -spiperone (70.3 Ci / mmol, 10 to 3000 pM final concentration) for 30 to 120 minutes at 22C in a total volume of 1. ml.

For comparison of binding experiments, assays are initiated by the addition of 0.75 ml membrane and incubated in duplicate with determined concentrations of competing ligands (10 ¹⁴ to 10 ¹³ M) and / or [ ³ H] -spiperone (100 to 300 pM) for 60 to 120 µM. minutes at 22 ^e C. Assays are terminated by rapid filtration through a Brandell cell harvester and the filters subsequently monitored for tritium as described by Sunahara, RK et al., (Nature, 1990, 346, 76).

For all experiments, specific [ ³ H] -spiperone binding is defined as binding inhibited by 1 to 10 mM (+) - butaclamol. Binding data is analyzed by a nonlinear least squares method. The compounds of the examples were tested in this assay and all were found to have binding affinities (K i) for [ ³ H] -piperone replacement of less than 2 micromolar.

Modulation of human D4 receptor by cAMP production

The Chinese hamster ovary (CHO) cells expressing the human D4 dopamine receptor were obtained from Dr. H. Van Tola (Čiarke Institute of Psychiatry, Toronto) and grown to confluence in minimal essential alpha-medium (Gibco) supplemented with 2.5% fetal bovine serum (non-heat inactivated), 2.5% horse serum (heat inactivated) and 500 pg / ml Geneticin.

The monolayers were ruptured and the cells released with 5 mM ethylenediaminetetraacetic acid (EDTA) and resuspended in phosphate buffered saline containing 5 mM magnesium chloride, 30 mM hydroxyethylpiperazine-N-ethanesulfonic acid (HEPES), 300 µΜ-1-methyl-3-methyl-3-methyl-3-methyl-3 IBMX, phosphodiesterase inhibitor), and 5.6 mM dextrose.

Cells (approximately 200,000 per tube) were exposed to 5 μΜ of forskolin (adenylate cyclase activator), forskin + test compounds, or quinpirol (D4 receptor agonist) or forskolin + quinpirol + antagonist for 11 minutes. In antagonist experiments, cells were exposed to antagonists 11 minutes before the agonist challenge.

The effect of the test compounds in the absence of quinpirole agonist was used to assess agonist activity. D4 ago antagonists inhibit cAMP accumulation, which can be reversed by D4 receptor antagonists. The reaction was terminated by the addition of 6N perchloric acid and samples neutralized with 5N potassium hydroxide and 2M tris buffer. Cyclic AMP levels were measured using a commercially available binding kit (Amersham).

IC ₅₀ values were calculated by linear regression analysis of concentration-response curves. were calculated using the equation:

= IC ₅₀ / (1 + [agonist] / [EC _5Q agonist]) (Minneman and Johnson, 1984).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is illustrated by the following examples, but is not limited to the details thereof.

Example 1

2- [4- (6-chloro-pyridazin-3-yl) piperazin-l-ylmethyl] -5-fluoro-indole

A mixture of 5 g of 5-fluoro-2-indolecarboxylic acid, 2.74 g of O-, N-dimethylhydroxylamine hydrochloride, 3.89 ml of triethylamine and 5.76 g of dicyclohexylcarbodiimide in 35 ml of methylene chloride is stirred at ambient temperature until a yellow-brown precipitate forms. . The solid was removed by filtration, the residue was concentrated and purified on SiO ₂ (25% EtOAc in hexanes) to give 3.6 g (64%) of N-O-dimethyl-2-indole hydroxide.

3.9 g of N-O-dimethyl-2-indolhydroxylamide are added over a period of minutes to a cold suspension (-40 ° C) of 0.67 g of LiAlH ₄ in 30 ml of tetrahydrofuran. The mixture was stirred for 1 hour (-40 ° C to -40 ° C)

-30'C), treated with saturated aqueous sodium sulfate and warmed to ambient temperature. The solvent was separated after addition of solid sodium sulfate and concentrated until a solid precipitate (2.94 g) of 5-fluoro-2-indolecarboxaldehyde was formed.

A mixture of 0.96 g of 4- (5-chlorophenyl) piperazine, 1.0 g of 5-fluoro-2-indolecarboxaldehyde and 1.2 g of triacetoxyborohydride in 50 ml of dichloroethane is stirred under a nitrogen atmosphere at ambient temperature for 48 hours. The solvent was removed and the residue was partitioned between 100 mL EtOAc and 20 mL NaOH (1N). The organic layer was washed with water (2 x 20 mL) and brine (1 x 10 mL) and concentrated. The residue was purified on SiO ₂ (eluent: 5% methanol in methylene chloride) to give 0.2 g of a cream-colored solid, mp 204-205 ° C.

Example 2 (5- [Fluoro-1H-indol-2-yl) - [4- (3-trifluoromethylphenyl) piperazin-1-yl] methanone

A mixture of 5 mmol of 5-fluoro-2-indolecarboxylic acid chloride and 230 mg of meta-trifluoromethylphenylpiperazine and 129 mg of diisopropylethylamine in 10 ml of methylene chloride is maintained at ambient temperature for 12 hours.

Water was added, the organic layer was separated, washed with water, dried over sodium sulfate and concentrated to afford 296 mg of the title compound. T. 198 ^e C.

Example 3

5-Fluoro-2- [4- (3-trifluoromethylphenyl) piperazin-l-ylmethyl] -1Hindolhydrochlorid

A solution of 275 mg of (5-fluoro-1H-indol-2-yl) - [4- (3-trifluoromethylphenyl) piperazin-1-yl] methanone in 5 ml of anhydrous tetrahydrofuran is kept under an inert gas atmosphere and treated at ambient temperature 2. 11 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran. After 12 hours, the mixture is treated with 78 μΐ of a 15% sodium hydroxide solution and again 234 μΐ of water. After addition of magnesium sulfate, the organic layer was separated and concentrated to a yellow oil (240 mg). This oil was dissolved in ether and treated with ethereal hydrochloric acid until a precipitate formed. The precipitate was collected and dried under vacuum.

The title compounds of Examples 4 and others were prepared by procedures analogous to those described in Examples 1-3.

Example 4

2- [4- (3-Trifluoromethylphenyl) piperazin-1-ylmethyl] -1H-indol-5-ol M.p. 188-190C, HRSMS 375.15.

Example 5

2- [4- (3-Trifluoromethylphenyl) piperazin-1-ylmethyl] -1H-indole m.p. 192 - 194'C, HRSMS 359.15.

Example 6 (1H-Indol-2-yl) - [4- (2-nitrophenyl) piperazin-1-yl] methanone mp 186-189 ^e C.

Example 7 (5-Fluoro-1H-indol-2-yl) - [4- (2-nitrophenyl) piperazin-1-yl] methanone

Tt. 184-188 ^e C.

Example 8 (5-Fluoro-1H-indol-2-yl) - [4- (3-trifluoromethylphenyl) piperazin-1-yl) methanone

T. 198 ^e C.

Example 9

3- [4- (1H-Indol-2-ylmethyl) piperazin-1-yl] benzo [d] isothiazole m.p. 150-152'C, HRSMS 348.12.

Example 10

5-Fluoro-2- [4- (3-trifluoromethylphenyl) piperazin-1-ylmethyl] -1H-indole m.p. 196-197’C, HRSMS 377,148.

Example 11

2- (4-naphthalen-l-yl-piperazin-l-ylmethyl) -lH-indole

MP: 238-239’C, HRSMS 341.19.

Example 12

2-14- (2-Nitrophenyl) piperazin-1-ylmethyl] -1H-indole

MP: 210-211'C, HRSMS 336.16.

Example 13

5-Fluoro-2- [4- (2-nitrophenyl) piperazin-1-ylmethyl] -1H-indole m.p. 236’C, HRSMS 354.14.

Example 14

5-Fluoro-2- (4-naphthalen-l-yl-piperazin-l-ylmethyl) -lH-indole

MP: 249-250’C, HRSMS 359.18.

Example 15

5-Fluoro-2- (4-pyridin-2-yl-piperazin-l-ylmethyl) -lH-indole

MP: 242’C, HRSMS 310.15.

Example 16

5-Fluoro-2- [4- (4-fluorophenyl) piperazin-1-ylmethyl] -1H-indole

MP:

»

Example 17

5-Fluoro-2- (4-pyrimidin-2-yl-piperazin-l-ylmethyl) -lH-indole Mp 199 C ^e, HRSMS 311.16.

Example 18 (5-Fluoro-1H-indol-2-yl) - (4-pyridin-2-ylpiperazin-1-yl) methanone m.p. 214-218'C.

Example 19

2- (4-Pyridin-2-yl-piperazin-l-ylmethyl) -lH-indole

MP:

Example 20 (1H-Indol-2-yl) - (4-pyridin-2-ylpiperazin-1-yl) methanone m.p. Mp 198-200 ° C.

Example 21

2- (4-Pyridin-2-ylpiperazin-1-ylmethyl) -1H-indole ¹³ C NMR (CDCl ₃ ), (75 MHz) d 45.29, 53.03, 55.96 107.29, 110.91 , 113.52, 119.70, 120.28, 121.69, 136.37, 137.61, 148.00, 159.55.

^T 1 HNMR (CDCl _3, 250 MHz) d 2.6 (m, 4H), 3.6 (m, 4H), 6.4 (s, IH), 6.7 (m, 2H), 7.1 -7.6 (m, 1H), 8.2 (m, 1H),

77.44, 101.94, 128.40, 135.53,

3.7 (s, 2H);

8.7 (br s, IH).

GC-MS, t _R = 4.488 min, M ⁺ = 292, (M-162) = 130.

Example 22 (2'α, 3 * ββ, 6'ap) -1- (4-Fluorophenyl) -4- (5'-phenyl-1 ', 2', 3 'a, 4', 6 'ahexahydropentalen-2 1'-yl] piperazine dihydrochloride Tt 250-253 ° C.

Analysis calculated for C24 ^H 27 ^FN 2 ^'2HC1 · ⁰ »H ₂ 0 ^75:

C 66.28, H 7.07, N 6.44

Found: C 66.18, H 6.76, N 6.56.

Example 23 (2'α, 3'ββ, 5'α, 6'ap) -5 '- [4- (4-Fluorophenyl) piperazin-1-yl] 2'-phenyl-octahydropentalen-2'-olmalate m.p. 206-207,5'C.

Analysis calculated for ^c 24 H ₂₉ FN ₂ 0.0.75 C ₄ H ₄ 0 ₂ .0.75 H ₂ O:

C 67.41, H 7.02, N 5.82

Found: C 67.24, H 6.77, N 5.68.

Example 24 (2'a, 3'ap, 5'a, 6 ') -1- (4-Fluorophenyl) -4- (5'-phenylooctahydropentalen-2'-yl) piperazine dihydrochloride m.p. 255-256,5'C.

Analysis calculated for C ₂₄ H ₂ FN ₂ · 2HCl · 0.25H ₂ O:

C 65.23, H 7.18, N 6.35.

Found: C 65.4, H 7.02, N 6.38.

Example 25 (2'a, 3'a3,5'a, 6 ^, ap) -2-Fluoro-4- [4- (5'-hydroxy-5'-phenyl-octahydropentalen-2'-yl) piperazin-1-yl ] -benzonitrile

MP: 207-207,5'C.

Analysis calculated for ^C 25 ^H 28 ^FN 3 ° - ^C 4 ^H 4 ° 4 ^:

C 66.78, H 6.18, N 8.06

Found: C 66.64, H 6.06, N 8.14.

Example 26 (2'a, 3'3β, 5'a, 6'ap) -2-Fluoro-4- [4- (3 ', 3'a, 4', 5 ', 6', 6'a- hexa hydrospiro [isobenzofuran-1 (3H) -2 '(1 ¹ H-pentalen] ^-5-1-yl) -1piperazinylJbenzonitrilmaleát

MP: 221 to 221.5 ° C.

Analysis calculated for ^C 26 ^H 28 ^FN 3 ° - ^C 4 ^H 4 ° 4 * ⁰ ' ^{5 H} 2 ^0:

C 66.41, H 6.13, N 7.74

Found: C 66.33, H 6.26, N 7.61.

Example 27 (2'α, 3'aP, 5'α, 6'ap) -5 '- [4- (2-Methoxyphenyl) piperazin-1-yl] 2'-phenyl-octahydropentalen-2'-olmalate m.p. 188-189'C.

Analysis calculated for C 25 ^H 32 ^N 3 ° 2 ^{, C} 4 ^H 4 ° 4 ^:

C 68.48, H 7.13, N 5.51

Found: C 68.64, H 7.10, N 5.81.

Example 28 (2'α, 3'ap, 5'α, 6'ap) -2- (4-Fluorophenyl) -5'- [4- (5-fluoropyrimidin-2-yl) piperazin-1-yl] octahydropentalene -2-2'-olmalate Tt 219,5-220'C.

Analysis calculated for ^C 22 ^H 26 ^F 2 ^N 4 ^{O, C} 4 ^H 4 ° 4 · ⁰ ' ^{5 H} 2 ^0:

C 59.41, H 5.94, N 10.66

C 59.76, H 5.89, N 10.65.

found:

Example 29 (2'α, 3'ββ, 5'α, 6'ββ) -2-Fluoro-4- {4- [5 '- (4-fluorophenyl) -5' hydroxyoctahydropentalen-2'-yl] piperazine- 1-yl] benzonitrile maleate

MP: 204 to 204.5 ° C.

Analysis calculated for ^C 25 ^H 27 ^F 2 ^N 3 ^{0, C} 4 ^H 4 ° 4 · ^Η 2 ^0:

C 62.47, H 5.97, N 7.54

Found: C 62.77, H 5.74, N 7.58.

Example 30 (2'a, 3 ^, ap, 5'a, 6'aP) -2 ^' - (4-Fluorophenyl) -5' - [4- (4-fluorophenylpiperazin-1-yl) octahydropentalen-2 '- olmalate Tt 209-209.5 ^e C.

Analysis calculated for C ₂₄ H ₂₈ F ₂ N ₂ OC ₄ H ₄ O ₄ :

C 65.36, H 6.27, N 5.54

Found: C 65.65, H 6.25, N 5.34.

Example 31 (2 ^, a, 3 ^, aP, 6 ^, ap) -5-Fluoro-2- [4- (5'-phenyl-1 ', 2', 3 ', 3'a, 4', 6'ahexahydropentalen- 2'-yl) piperazin-1-yl] pyrimidine maleate Mp: 202-203 ° C.

Analysis calculated for C ₂₂ H ₂₅ FN ₄ .C ₄ H ₄ O ₄ :

C 64.99, H 6.08, N 11.66

Found: C 64.67, H 6.00, N 11.79.

EXAMPLE 32 (2'a, ^3'a3,6, p) 2-Fluoro-4- [4- ^(5-phenyl-I ', ^2', 3 ', 3' and 4 ', ^6, ahexahydropentalen- 2'-yl) piperazin-1-yl] benzonitrile maleate

MP: 172-173'C.

Analysis calculated for ^C 25 ^H 26 ^FN 3 ' ^C 4 ^H 4 ° 4 ^:

C 69.17, H 6.00, N 8.34

Found: C 69.06, H 5.88, N 8.57.

Example 33 (2'α, 3'ap, 5'α, 6'ap) -5-Fluoro-2- [4- (5'-phenylooctahydropentalen 2'-yl) piperazin-1-yl] pyrimidine maleate Tt: 211,5- 212'C.

Analysis calculated for ^C 22 ^H 27 ^FN 4 ^{, C} 4 ^H 4 ° 4 ^:

C 64.72, H 6.48, N 11.61

Found: C 64.67, H 6.43, N 11.82.

Example 34 (2'a, 3'ap, 5'a, 6 ^, ap) -2-Fluoro-4- [4- (5'-phenylooctahydropentalen-2'-yl) piperazin-1-yl] benzonitrile maleate Tt: 195- 196'C.

Analysis calculated for ^C 25 ^H 28 ^FN 3 ^-C 4 ^H 4 ^O:

C 68.89, H 6.38, N 8.31

Found: C 68.99, H 6.47, N 8.30.

Example 35 (2'α, 3'ap, 5'α, 6'ap) -2-Fluoro-4- {4- [5 '- (2-trifluoromethylphenyl) octahydropentalen-2'-yl] piperazin-1-yl } benzonitrile maleate Tt 192-193'C.

found:

Analysis calculated for C ₂₆ H ₂₇ F ₄ N ₃ .C ₄ H ₄ O ₄ :

C 62.82, H 5.45, N 7.33

C 62.87, H 5.22, N 7.27.

Example 36 (2'α, 3'ββ, 5'α, 6'ββ) -2-Fluoro-4- {4- [5- (2-methoxyphenyl) -1 ', 2', 3 ', 3'a 4 ', 6'a-hexahydropentalen-2'-yl} piperazin-1-yl] benzonitrile maleate

Tt 155-156 ^e C.

Analysis calculated for ^C 26 ^H 28 ^FN 3 ° 4 · ⁰ · ^{25 H} 2 ^0:

C 66.96, H 6.09, N 7.81

Found: C 67.0, H 6.05, N 7.82.

Example 37 (2'α, 3'ββ, 5'α, 6'ββ) -2-Fluoro-4- {4- [5 '- (2-methoxyphenyl) octahydropentalen-2'-yl} piperazin-1-yl ] benzonitrile maleate Tt 176-177-C.

Analysis calculated for ^C 26 ^H 30 ^FN 3 ° - ^C 4 ^H 4 ° 4 * ^{0 '50 H 20:}

C 66.16, H 6.48, N 7.71

Found: C 66.20, H 6.31, N 7.69.

Example 38 (2'α, 3'3β, 5'α, 6'3β) -2-Fluoro-4- {4- [5 '- (1H-indol-3-yl) octahydro-pentalen-2'-yl] -piperazine- 1-ylbenzonitrile maleate Tt 226-227'C.

Analysis calculated for ^C 27 ^H 29 ^FN 4 * ^C 4 ^H 4 ° 4 ^:

C 68.37, H 6.11, N 10.29

Found: C, 68.17; H, 6.24; N, 10.20.

Example 39 (2'α, 3'ββ, 5'α, 6'ββ) -2-Fluoro-4- {4- [5 '- (2-methanesulfonylphenyl) octahydropentalen-2'-yl] piperazin-1-yl } -benzonitrile

MP: 179-180'C.

Analysis calculated for ^C 26 ^H 30 ^FN 3 ° 2 ^{S, C} 4 ^H 4 ° 4 · ^{0 '25 H} 2 ^0:

C 61.25, H 5.91, N 7.14

Found: C 61.26, H 6.32, N 6.76.

Example 40 (2 "and 3" p, · β 5, 6 and p ¹⁾ 2-Fluoro-4- [4- (3 ·, 3 ^, 4 ^ 5 ^ ¹ 6, 6'a-hexahydrospiro [isobenzofuran -1 (3H) -2 '(1 ^1H) -pentalen] -5'-yl) -1piperazinylJbenzonitrilmaleát

MP: > 260’C.

Analysis calculated for ^C 26 ^H 28 ^FN 3 ° ^-CH 4 ° 3 ^S:

C 63.14, H 6.27, N 8.18

Found: C 63.12, H 6.66, N 8.00.

Example 41 (2'a, 3'ap, 5'a, 6'aP) -2-Fluoro-4- [4- (3,3 ', 3'a, 4,4', 5 ', 6', 6'ahexahydrospiro [2H '-1-benzopyran-2,2' (1'H) -pentalen] -5'-yl) -1 piperazinyl] benzonitrile maleate

MP: 176-177'C.

Analysis calculated for ^C 27 ^H 28 ^FN 3 ° 2- ^C 4 ^H 4 ° 4 · ^{0 '50 H} 2 ^0:

C 65.25, H 5.82, N 7.36

Found: C 65.52, H 6.06, N 7.19.

Example 42 (2'a, 3'ap, 5'p, 6'aP) -2-Fluoro-4- [4- (3,3'a, 4,4 ', 5', 6 ', 6'ahexahydrospiro) [2H-1-benzopyran-2,2 ¹ (1'H) pentalen] -5'-yl) 1-piperazinyl] benzonitrile maleate

MP: 179-180'C.

found:

Analysis calculated for C ₂₇ H ₂₈ FN ₃ O ₂ .C ₄ H ₄ O ₄ :

H, 5.74; N, 7.48

C 66.17, H 6.07, N 7.34.

Example 43 (2 * α, 3'Ββ, 5'α, 6 'ap) -2-Fluoro-4- {4- [5' - (2-trifluoromethoxyphenyl) octahydropentalen-2 'yl] piperazin-1 -yl} benzonitrile maleate Tt 126-129'C.

NMR DMSO dgl δ 7.70 (t, J = 8.5Hz, 1H), 7.52 (d, J = 7.1Hz, 1H),

7.40-7.25 (m, 3H), 7.09 (d, J = 13.6Hz, 1H), 6.96 (d, J = 9, J, 1H), 6.06 (s, 2H) 1.73-2.90 (br m, 108), 2.65-2.54 (m, partially under DMSO, 1H), 2.46-2.18 (m, 4H), 1.63- 1.42 (m, 4H).

Example 44 (2 * α, 3 ^, αβ, 5 ^, α, 6'3β) -2-Fluoro-4- {4- [5 '- (2-fluorophenyl) octahydro-pentalen-2'-yl] piperazine- 1-yl) benzonitrile maleate mp 179-180.5 ° C.

Analysis calculated for ^C 25 ^H 27 ^F 2 ^N 3 ^{, C} 4 ^H 4 ^O:

C 66.53, H 5.97, N 8.03

Found: C, 66.62; H, 6.24; N, 7.98.

Example 45 (2'α, 3 ^, 3β, 5'α, 6'β) -2-Cyano-4- {4- [5 '- (2-fluorophenyl) octahydropentalen-2'-yl] piperazin-1 -yl} benzonitrile maleate mp 193-194 ° C.

Analysis calculated for ^C 26 ^H 27 ^FN 4 · ^C 4 ^H 4 ° · ⁰ · ^{50 H} 2 ^0:

C 66.76, H 5.98, N 10.38

Found: C 66.99, H 6.05, N 10.34.

Example 46 (2 'and 3' ββ, 5.'a, 6 ¹ ββ) -2-Fluoro-4- [4- (5'-pyridin-2-yloktahydropentalen-2'-yl) -piperazin-l-yl ] benzonitrile dihydrochloride

Mt 203-206 ^e C.

For C ₂₄ H ₂₇ FN ₄ O ₂ .2HC1.H:

C 59.88, H 6.49, N 11.63

Found: C 59.55, H 6.42, N 11.47.

Example 47 (2'α, 3'ap, 5'α, 6'ap) -5-Fluoro-2- {4- [5 '- (2-methoxyphenyl) octahydro-pentalen-2'-yl] piperazin-1- yl} pirimidine maleate Tt 183.5-184.5 ° C.

Analysis calculated for C ₂₃ H ₂ FN ₄ OC ₄ H ₄ O ₄ :

C 63.26, H 6.49, N 10.93

Found: C 63.21, H 6.71, N 10.82.

Example 48 (2'aa, 3'aP, 5'α, 6'ap) -2-Fluoro-4- {4- [5 '- (6-fluoro-2-oxo-2,3-dihydrobenzoimidazole-1- yl) octahydropentalen-2'-yl] piperazin-1-yl] benzonitrildimezylate

MP: 219-222'C.

Analysis calculated for ^C 26 ^H 27 ^FN 5 ° ^-2CH 4 ° 3 ^S:

C 51.29, H 5.38, N 10.68

Found: C 51.84, H 5.57, N 10.64.

Example 49 (2'a, 3'ap, 5'a, 6 ^, aP) -2-Fluoro-4- {4- [5 '- (6-fluoro-2-methylbenzoimidazol-1-yl) octahydropentalen-2' yl] -piperazin-l-ylJbenzonitrildimezylát

MP: > 260’C.

Analysis calculated for c ₂₇ H ₂ F ₂ N ₅ .2CH ₄ O ₃ S.0.50 H ₂ 0:

H, 5.48; N, 10.57. Found: C, 52.64; H, 5.71; N, 10.57.

Example 50 ⁽¹ and 2, 3'ap, 5'α, 6'ap) -5-Fluoro-2- [4- (3 ', 3' and 4 ', 5', 6 ', 6' a- hexahydrospiro [isobenzofuran-1- (3H), 2 '(1'H) pentalen] -5'-yl) piperazin-1-yl] pyrimidine

Tt 186 ^e C.

NMR CDD1 ₃ : δ 8.20 (s, 2H), 7.25-7.17 (m, 4H), 7.12-7.09 (m, 1H), 5.00 (s, 2H), 3 , 79-3.71 (m, 4H), 2.72-2.44 (m, 7H), 2.20-2.13 (m, 2H), 2.17-1.93 (m, 2H) 1.69-1.67 (s, 2H).

Example 51 (2 'P, 3'aP, 5'a, 6'aP) -5-Fluoro-2- [4- (3', 3'a, 4 ', 5', 6 ', 6'a- hexahydrospiro [isobenzofuran-1- (3H), 2 '(1'H) -pentalen] -5'-yl) piperazin-1-yl] pyrimidine

MP: 186-187C.

NMR CDCl ₃ : δ 8.18 (s, 2H), 7.26-7.10 (m, 3H), 7.08-7.06 (m, 1H), 5.10 (S, 2H), 3 , 78-3.76 (br s, 4H), 2.78-2.73 (m, 2H), 2.66-2.54 (m, 5H), 2.32-2.22 (m, 4H) 1.74-1.66 (m, 2H), 1.38-1.29 (m, 2H).

Example 52 (2'a, 3'ap, 5 'a, 6'ap) -1-Phenyl-4- (3,3', 3'a, 4,4 ', 5', 6 ', 6'a) -hexa hydrospiro [2H-1-benzopyran-2,2 '(1'H) -pentalen] -5'-yl] -5' yl) piperazine maleate

MP: 200-201'C.

Analysis calculated for C ₂₆ H ₃₀ N ₂ O ₂ .C ₄ H ₄ O ₄ :

C 69.48, H 6.61, N 5.40

C 69.48, H 6.80, N 5.44.

found:

Example 53 (2'β, 3'ap, 5'α, 6 ¹ ββ) -l-phenyl-4- (3,3 ', 3 &apos;,4,4', 5 ', 6', 6 ' -hexahydrospiro [2H-1-benzopyran-2,2 '(1'H) -pentalen] -5'-yl] -5'-yl) piperazine maleate

MP: 220-221'C.

Analysis calculated for ^c 26 ^H 30 ^N 2 ° 2 ' ^c 4 ^H 4 ° 4 ^:

C 69.48, H 6.61, N 5.40

Found: C 69.28, H 6.84, N 5.33.

Example 54 (2'a, 3'a3,5'a, 6'ap) -3- [5 '- (4-Phenylpiperazin-1-yl) octahydropentalen-2'-yl] -1H-indole maleate m.p. 232 to 232.5 "C.

Analysis calculated for ^C 26 ^H 31 ^N 3 ^{, C} 4 ^H 4 ° 4 ^:

C 71.83, H 7.03, N 8.38

Found: C 71.57, H 7.38, N 8.31.

Example 55 (2 ^, a, 3'ap, 6'ap) -1-Phenyl-4- (5'-phenyl-1 ', 2', 3 ', 3', 4 ', 6'-hexahydropentalen-2'-yl) piperazin maleate Tt 156-157 ° C.

Analysis calculated for ^C 26 ^H 30 ^N 2 ° 2 · ^2C 4 ^H 4 ° 4 ^:

C 66.65, H 6.29, N 4.86

Found: C 66.27, H 6.57, N 5.00.

Example 56 (2'a, 3'ap, 5'a, 6'ap) -1-Phenyl-4- (5'-phenylooctahydropentalen-2'-yl) piperazine Maleate m.p. 217-218'C.

Analysis calculated for C ₂₄ H ₃₀ N ₂ .C ₄ H ₄ O ₄ :

C 72.70, H 7.41, N 6.06

Found: C 72.28, H 7.46, N 6.01.

Example 57 (2 ^, a, 3'ap, 5'a, 6'ap) -6-Fluoro-2-methyl-1- [5 '- (4-phenylpiperazine)

1-yl) octahydropentalen-2'-yl] -1H-benzoimidazole maleate m.p. 203-205'C.

Analysis calculated for ^C 26 ^H 31 ^FN 4 * ^2C 4 ^H 4 ° 4 ' ⁰ ' ^{50 H} 2 ^0:

C 61.90, H 6.11, N 8.49

Found: C 61.96, H 6.01, N 8.58.

Example 58 (2'a, 3'ap, 5'p, 6'ap) -1- [5 '- (4-Fluorophenoxy) octahydropentalen-2'-yl) -4-phenylpiperazine maleate m.p. 177-178'C.

Analysis calculated for ^C 24 ^H 29 ^FN 2 ° ^C 4 ^H 4 ° 4 ^:

C 67.72, H 6.70, N 5.64

Found: C 67.33, H 6.82, N 5.62.

Example 59 (2'a, 3'ap, 5'p, 6'ap) -2- [5 '- (4-Phenylpiperazin-1-yl) octahydropentalen-2'-yl] isoindole-1,3-dione maleate m.p. 235,5-236'C.

Analysis calculated for C ₂₆ H, _{2 g} of N ₃ O ₂ .C ₄ H ₄ O _4:

C 67.78, H 6.26, N 7.90

Found: C 67.71, H 6.37, N 7.94.

Example 60 (2'a, 3 ^, ap, 5 ^, a, 6 ^, ap) -N- (2- {5 '- [4- (5-Fluoropyrimidin-2-yl) piperazin-1-yl] octahydropentalen-2 1-yl} phenyl) acetamide maleate mp 211.5-212 ° C.

Analysis calculated for ^C 24 ^H 30 ^FN 5 ° - ^C 4 ^H 4 ° 4 ^:

C 62.33, H 6.35, N 12.98

Found: C 62.07, H 6.32, N 12.87.

Example 61 (2'a, 3'ββ, 5'a, 6'ββ) -N- (2- {5 '- [4- (4-cyano-3-fluorophenyl) piperazin-1-yl] octahydropentalen-2) 1-yl} phenyl) acetamide maleate Tt 197-199.

Analysis calculated for C27H31FN4O.C4H4O4:

C 66.18, H 6.27, N 9.96

Found: C 66.06, H 6.20, N 9.89.

Example 62 (2 ^, α, 3 ^, 3β, 5'ο, 6'3β) -2-Fluoro-4-4- [5 '- (2-oxo-2,3-dihydrobenzoimidazol-1-yl) octahydropentalen-2 'yl] -piperazin-l-ylbenzonitrilmezylát

MP: higher than 260’C.

Analysis calculated for C ₂₆ H ₂₈ FN ₅ O.CH ₄ O ₃ S.0.50 H ₂ O:

C 58.89, H 6.04, N 12.72

Found: C 59.01, H 6.06, N 12.71.

Example 63 (2'a, 3'ββ, 5'a, 6'ββ) -1- {5 '- [4- (5-Fluoropyrimidin-2-yl) piperazin-1-yl] octahydropentalen-2'-yl} - l, 3-dihydro-benzoimidazol-2-onmezylát

Mp> 260 ^e C.

Analysis calculated for ^C 23 ^H 27 ^FN 6 ° ^-CH 4 ° 3 ^S:

C 55.58, H 6.04, N 16.20

Found: C 55.48, H 5.87, N 16.41.

Example 64 (2'α, 3'ββ, 5'α, 6'ap) -2- {5 * - [4- (4-Cyano-3-fluorophenyl) piperazin-1-yl] octahydropentalen-2'-yl} benzamide maleate Tt 198,5-200 ^e C.

Analysis calculated for C 26 ^ 29 ^ ^^ 4 C4H4O4.0,50 _H2O:

C 64.62, H 6.15, N 10.05

Found: C 64.84, H 6.01, N 10.03.

Example 65 (2'α, 3'ββ, 5'α, 6'ap) -N- [5 '- (4-Phenylpiperazin-1-yl) octahydropentalen-2'-yl] benzamide maleate Tt 211-212.5 ^e c.

For C ₂₅ H ₃₁ N ₃ OC ₄ H ₄ O ₄ .0.25 H _2:

C 68.28, H 7.01, N 8.23

Found: C 68.17, H 6.94, N 8.18.

Example 66 (Ζ'α, Β'Ββ, δ'β, β'Ββ) -2-Fluoro-4- {4- [5 '- (4-fluorophenoxy) octahydropentalen-2'-yl] pipera from in-1 -yl} benzonitrile maleate Tt 192-193'C.

found:

Analysis calculated for ^C 25 ^H 27 ^F 2 ^N 3 ^{O, C} 4 ^H 4 ° 4 ^:

C 64.55, H 5.79, N 7.79

C 64.50, H 5.80, N 7.71.

Example 67 (2'α, 3'ββ, 5'β, 6'ββ) -5-Fluoro-2- {4- [5 '- (4-fluorophenoxy) octahydropentalen-2'-yl] piperazin-1-yl] pyrimidine maleate Tt 192-194'C.

Analysis calculated for ^C 22 ^H 26 ^F 2 ^N 4 ^{O, C} 4 ^H 4 ° 4 ^:

C 60.46, H 5.85, N 10.85

Found: C 60.30, H 5.82, N 10.78.

Example 68 (2 ¹ α, 3'3β, 5 'β, 6' ap) -2-Fluoro-4- {4- [5 - (2-oxo-2,3-dihydrobenzoimidazol-1-yl) octahydropentalene- 2'-yl] piperazin-1-yl} benzonitrile maleate

MP: 170-177 ° C.

NHR DMSO d _g : δ 10.89 (s, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.30-7.23 (m, 1H), 7.1 (d, J) = 13.9Hz, 1H), 7.04-6.93 (m, 4H), 6.06 (s, 2H),

4.97-4.82 (m, 1H), 3.62-2.80 (br m, 10H), 2.75-2.63 (m, 2H),

2.60-2.50 (m, partially under DMSO peak, 1H), 2.48-2.36 (m, 2H), 1.60 (dd, J ₁ = 12.4Hz, J ₂ = 6.6Hz (2H), 1.58-1.34 (m, 2H).

Example 69 (2'α, 3 ^, 3β, 5 ^, α, 6'3β) -2-Fluoro-4- {4- [5 '- (3-methoxyphenyl) octahydropentalen-2'-yl] piperazin-1-yl } benzonitrile maleate Tt 169-170 ° C.

Analysis calculated for ^C 26 ^H 30 ^FN 3 ° ^-C 4 ^H 4 ° 4 ^:

C 67.27, H 6.40, N 7.85 C 67.18, H 6.52, N 7.87.

found:

Example 70 (4 ', 4', 8 ', 8'), 2-Fluoro-4- {4- [5 '- (4-methoxyphenyl) octahydro-pentalen-2'-yl] piperazin-1-yl} -benzonitrile

MP: 186 to 186.5 ° C.

For ^C 26 ^H 30 ^F1í 3 ° ^'C 4 ^H 4 ° 4' 0/25 HjOí C 66.71, H 6.44, N 7.78

Found: C 66.70, H 6.60, N 7.60.

Example 71 (2'α, 3 * 3β, 5 ^, α, 6 ^, 3β) -2-Fluoro-4- [4- (5'-m-tolylooctahydropentalen-2'-yl) piperazin-1-yl] benzonitrile maleate Tt 198 to 198.5 ° C.

Analysis calculated for ^C 26 ^H 30 ^FN 3 ^-C 4 ^H 4 ° 4 ^:

C 69.35, H 6.60, N 8.09

Found: C 69.48, H 6.74, N 8.14.

Example 72 (2'α, 3'ap, 5'α, 6'ap) -2-Fluoro-4- [4- (5'-p-tolyloctahydropentalen-2'-yl) piperazin-1-yl] benzonitrile maleate m.p. 194-195'C.

NMR DMSO d _6: δ 7.70 (t, J = 8.5 Hz, IH), 7.16-7.09 (m, 5H), 6.96 (d, J = 8.7 Hz, IH), 6 2.65 (s, 2H), 3.75-2.85 (m, 11H), 2.55-2.43 (m, partially under DMSO peak, 1H), 2.40-2.23 (m with singlet Q2) 26.7H in total), 1.63-1.32 (m, 4H).

Example 73 (2'β, 3'aP, 5'β, 6'a3) -1- [5 '- (4-Fluorophenoxy) octahydropentalen-2'-yl] -4-phenylpiperazine Maleate m.p. 174-175'C.

Analysis calculated for ^C 24 ^H 29 ^FN 2 ° - ^C 4 H 4 ° 4 ^:

C 67.72, H 6.70, N 5.64

Found: C 67.82, H 6.83, N 5.59.

Example 74 (2 '<x, 3' ap, 5 'α, 6' ap) -2-Fluoro-4- [4- (5'-o-tolylooctahydropentalen-2'-yl) piperazin-1-yl] benzonitrile maleate Tt 198-199'C.

Analysis calculated for ^C 26 ^H 30 ^FN 3 ^-C 4 ^H 4 ° 4 ^:

C 69.35, H 6.60, N 8.09

Found: C 69.13, H 6.69, N 8.12.

Example 75 (2 'α, 3' ap, 5 'α, 6' ap) -1-Phenyl-4- [5 '- (3-pyrrolidin-1-ylmethylphenyl) octahydropentalen-2'-yl] piperazinedimaleate m.p. 163,5-164'C.

Analysis calculated for C ₂₉ H ₃ FN ₃ .2C ₄ H ₄ O ₄ :

C 67.15, H 7.16, N 6.35

Found: C 66.81, H 7.22, N 6.27.

Example 76 (2 'a, 3 ^, ap, 5' a, 6 ^, ap) -5-Fluoro-2- [4- (3 ', 3' a, 4 ', 5', 6 ', 6' - hexahydro-3 &apos;, 6 & apos-dimethyl-spiro [isobenzofuran-l (3H), 2 '(l'H) -pentalen] -5'-yl) -1-piperazinylIpyrimidín

T.t.224,5-225'C.

Analysis calculated for C ₂₅ H ₃₁ FN ₄ OC ₄ H ₄ O ₄ .0.25 H ₂ O:

C 64.13, H 6.59, N 10.32. C 64.25, H 6.68, N 10.14.

found:

Example 77 (2 'α, 3'ap, 5'a, 6'ap) -5-Fluoro-2- [4- (3', 3'a, 4 ', 5', 6 ', 6'a- hexahydro-3 'a, 6'a-dimethylspiro [isobenzofuran-1 (3H), 2' (1'H) pentalen] -5'-yl) -1-piperazinyl] pyrimidine maleate

MP: 222-223'C.

NMR DMSO d _g: δ 8.58 (s, 2H), 7.34-7.30 (m, 1H), 7.28-7.25 (m, 3H), 6.04 (s, 2H); 4.94 (s, 2H), 3.65-2.75 (br m, 9H), 2.20-2.12 (m, 2H), 1.94 (AB quartet, Δ> i = 37.8Hz J = 13.2Hz, 4H), 1.54 (br t, J = 11.7Hz, 2H), 1.21 (s, 6H).

Example 78 (2 'α, 3 ¹ ap, 5' β, 6 ¹ ap) -4- {4- [5 ^1- (1,3-dioxo-1,3-dihydroisoindol-2-yl) octahydropentalen-2'-yl] piperazin-1-yl} -2-fluorobenzonitrile maleate

MP: 224 to 224.5 ° C.

Analysis calculated for ^C 27 ^H 27 ^FN 4 ° 2 ^{, C} 4 ^H 4 ° 4 ^:

C 64.80, H 5.44, N 9.75

Found: C 64.85, H 5.56, N 9.74.

Example 79 (2'α, 3'ap, 5'β, 6'ap) -2- {5 '- [4- (5-Fluoropyrimidin-2-yl) piperazine

1-yl] octahydropentalen-2'-yl} isoindole-1,3-dione maleate m.p. 241.5 to 242 "C.

Analysis calculated for ^C 24 ^H 26 ^FN 5 ° 2 · ^C 4 ^H 4 ° 4 ^:

C, 60.97; H, 5.48; N, 12.70; C, 60.66; H, 5.55; N, 12.44.

found:

Example 80 (2 * α, 3 'ap, 5 * α, 6' ap) -2-Fluoro-4- [4- (3,3 ', 3'a, 4,4', 5 ', 6', 6'ahexahydrospiro [2H-6-fluoro-1-benzopyran-2,2 '(1, H) -pentyl] 5'-yl] -5'-yl) -1-piperazinyl] benzonitrile maleate

MP: 219-220'C.

Analysis calculated for ^C 24 ^H 26 ^F 2 ^N 4 ° 2 · ^C 4 ^H 4 ° 4 · ^{0 '50 H} 2 ^0:

C 59.46, H 5.55, N 9.90

Found: C 59.86, H 5.70, N 9.40.

Example 81 (2'P, 3'ap, 5'a, 6'ap) -2-Fluoro-4- [4- (3,3 ', 3'a, 4,4', 5 ', 6', 6'ahexahydrospiro [2H-6-fluoro-1-benzopyran-2,2 ¹ ( ¹ H) -pentyl] 5'-yl] -5'-yl) -1-piperazinyl] benzonitrile maleate

MP: 216,5-217'C.

Analysis calculated for ^C 24 ^H 26 ^F 2 ^N 4 ° ^2'C 4 ^H 4 ° 4 ^:

H, 5.43; N, 10.07. Found: C, 60.39; H, 5.47; N, 9.90.

Example 82 (2'α, 3'ap, 5'α, 6'ap) -5-Fluoro-2- [4- (5'-o-tolyloctahydropentalen-2'-yl) piperazin-1-yl] pyrimidine maleate Mp 204-205'C.

Analysis calculated for ^C 23 ^H 29 ^FN 4 · ^C 4 ^H 4 ° 4 ^:

C 65.31, H 6.70, N 11.28. C 65.38, H 6.77, N 11.32.

found:

Example 83 (2'β, 3'ap, 5'α, 6'ap) -1- {5 '- [4- (4-Fluorophenyl) piperazin-1-yl] octahydropentalen-2'-yl} -1, 3-dihydrobenzoimidazol-2-one maleate Tt 217-218 ^e C.

Analysis calculated for ^C 25 ^H 29 ^FN 4 ° - ^C 4 ^H 4 ° 4 ^:

C 64.91, H 6.20, N 10.44

Found: C 64.57, H 6.28, N 10.18.

Example 84 (2'β, 3'ap, 5'α, 6'ap) -2- [5 '- (4-phenylpiperazin-1-yl) octahydropentalen-2'-yloxy] -1H-benzoimidazole maleate m.p. 161-162'C.

Analysis calculated for C ₂₅ H ₃₀ N ₄ OC ₄ H ₄ O ₄ :

C 67.16, H 6.61, N 10.80

Found: C 67.05, H 6.66, N 10.59.

Example 85 (2'a, 3, aP, 5'a, 6'aP) -5-Chloro-2- {4- [5 '- (2-methoxyphenyl) octahydropentalen-2'-yl] piperazin-1-yl } pyrimidine maleate Tt 199,5-200 ^e C.

Analysis calculated for ^C 23 ^H 29 ^ClN 4 ^{O, C} 4 ^H 4 ° 4 ^:

C 61.30, H 6.29, N 10.59

Found: C 61.05, H 6.31, N 10.83.

EXAMPLE 86 (α 2 ^1, 3 ¹ p, 5 'α, 6 "p) of 5-chloro-2- [4- (5-O-tolyloktahydropentalen2'-yl) piperazine-l-ylJpyrimidínmaleát Mp 200-200. 5 DEG.

Analysis calculated for C ₂ ^H 29 ^ClN 4 ^-C 4 ^H 4 ° 4 ^:

C 63.21, H 6.48, N 10.92

Found: C 62.97, H 6.33, N 11.29

Example 87 (2'P, 3'ap, 5'd, 6'ap) -2- {5 '- [4- (3,4-Difluorophenyl) piperazin-1-yl] octahydropentalen-2'-yl} isoindol-1 , 3-dione maleate Tt 221,5-222'C.

Analysis calculated for ^C 26 ^H 27 ^F 2 ^N 3 ° 2 ^{, C} 4 ^H 4 ° 4 ^:

C 63.48, H 5.51, N 7.46

Found: C 63.28, H 5.51, N 7.64.

Example 88 (2 'β, 3'ap, 5'α, 6'& β) -2- {5' - [4- (4-Fluorophenyl) piperazin-1-yl] octahydropentalen-2'-yl} isoindole-1 , 3-dione maleate Tt 209-210'C.

Analysis calculated for ^C 26 ^H 28 ^FN 3 ° 2- ^C 4 ^H 4 ° 4 ' ⁰ ' ^{50 H} 2 ^0:

C 64.51, H 5.95, N 7.52

Found: c 64.47, H 5.91, N 7.66.

Example 89 (2'β, 3 * ap, 5'α, 6'ap) -1- {5 '- [4- (3,4-Difluorophenyl) piperazin-1-yl] octahydropentalen-2'-yl} -1, 3-dihydro-benzoimidazol-2-one maleate

MP: 201-202 "C.

Analysis calculated for ^C 25 ^H 28 ^F 2 ^N 4 ° 4 ^{, C} 4 ^H 4 ° 4 * ^{0 '50} H ₂ O:

C 61.10, H 5.90, N 9.94 C 62.10, H 5.80, N 9.56.

found:

Claims (21)

A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the dashed line represents an optional double bond, and is 0 or 1, wherein when a is 0, X may form an optional double bond with carbon adjacent to V, V is CHR ³ · ^O where R ^3-8 is hydrogen or (C 1 -C 8) alkyl, T is nitrogen or CH, X is nitrogen or CR ¹¹ where R ¹¹ is hydrogen, (C ₁ -C 6) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy or cyano, Y and Z are each independently nitrogen or CR ¹² wherein R ¹² is hydrogen, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C _{1 -C)} alkoxy, or (C ^ -C) alkyl, R ¹ is hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano or (C 1 -C 6) alkyl, R ² , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 8) alkoxy and (C 1 -C 8) alkyl. R ³ and R ⁴ are each independently hydrogen or (C 1 -C 8) alkyl, and R ⁵ is hydrogen, (C 1 -C 6) alkoxy, trifluoromethyl, cyano, (C 1 -C 6) alkyl or R ¹³ CO-, wherein R ¹³ is amino, (C 1 -C 6) alkylamino, ((C 1 -C 6) alkyl) ₂ amino, (C 1 -C 6) alkyl, (C 1 -C 6 aryl), or when a is 1, R ¹ and R ¹⁰ may be taken together with the carbons to which they are attached to form a compound of formula II wherein the dotted lines represent optional bonds, T, X, Y, Z, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above, b is 0 or 1, A and B are each subject to no, subject to no, and subject to sulfur. and independently CH, CH ₂ , oxygen, sulfur, NH or nitrogen when X is nitrogen, the optional double bond between X and V when b is 0, the optional double bond between A and B when b is 1, A and B cannot both oxygen or A compound according to claim 1, wherein The compound of claim 1, wherein R ¹² is nitrogen or fluoro. A compound according to claim 1, wherein or chlorine. The compound of claim 1, wherein The compound of claim 1, wherein A compound according to claim 1, wherein or alkoxy. The compound of claim 1, wherein X is nitrogen. Y and Z are each CR ¹² , R ¹² is hydrogen, fluoro R ³ , R ⁴ and R ⁵ are hydrogen. R ⁷ is fluoro or chloro. R 6 is fluoro, chloro, bromo X is nitrogen, Y and Z are each CR ¹² wherein R ¹² is hydrogen or fluoro, R ² is hydrogen, fluoro or chloro, R ³ , R ⁴ and R ⁵ are hydrogen, R ⁷ is fluoro or chloro and R ⁷ is fluoro, chloro, bromo or alkoxy. The compound of claim 1, wherein the compound is selected from the group consisting of 2- [4- (3-Trifluoromethylphenyl) -piperazin-1-ylmethyl] -1H-indole, 5-fluoro-2- [4- (3-trifluoromethylphenyl) piperazin-1-ylmethyl] -1H-indole, 5-fluoro-2- [4- (4-fluorophenyl) piperazin-1-ylmethyl] -1H-indole, 5-fluoro-2- [4- (4-fluorophenyl) piperazin-1-ylmethyl] -1H-indole, 5-fluoro-2- (4-pyridin-2-ylpiperazin-1-ylmethyl) -1H-indole, 2- [4- (6-chloropyridazin-3-yl) piperazin-1-ylmethyl] -5-fluoro-1H-indole, 5-fluoro-2- (4- [5-fluoro ^1] pyridin-2-yl-piperazin-l-ylmethyl) indole-ΙΗ, 2- (4-pyridin-2-yl-piperazin-l-ylmethyl) -ΙΗ-azaindole, 5-fluoro-2- (4-pyridin-2-ylpiperazin-1-ylmethyl) -ΙΗ-azaindole, and 2- [4- (4-fluorophenyl) piperazin-1-ylmethyl] -ΙΗ-azaindole. 10. A method of treating a dopamine system disorder in a mammal, comprising administering to said mammal an amount of a selective dopamine receptor D4 compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is effective in treating such disorder. The method of claim 10, wherein the dopamine system disorders include psychotic disorders, movement disorders, gastrointestinal disorders, chemical abuse, chemical dependence, substance abuse, vascular and cardiovascular disorders, ocular disorders and sleep disorders. 12. A method of treating a dopamine system disorder in a mammal comprising administering to said mammal an amount of a selective dopamine receptor D4 compound according to claim 1, or a pharmaceutically acceptable salt thereof, in association with one or more dopamine receptor D1, D2, D3 or D5 agonists. which is effective in treating such a disorder. The method of claim 12, wherein the dopamine system disorders include psychotic disorders, movement disorders, gastrointestinal disorders, chemical abuse, chemical dependence, substance abuse, vascular and cardiovascular disorders, ocular disorders and sleep disorders. The method of claim 11, wherein the psychotic disorders include affective psychoses, schizophrenia, and schizoaffective disorders. 15. The method of claim 11 wherein _E characterized in that the movement disorders include extrapyramidal side effect of neuroleptic agents, neuroleptic malignant syndrome *, tardive dyskinesia, Gilles de la Tourette's syndrome, Parkinson's disease or Huntington's disease. 16. The method of claim 11, wherein the gastrointestinal disorders include gastric acid secretion or vomiting. 17. The method of claim 11, wherein the vascular and cardiovascular disorders include multiple heart failure and hypertension. 18. A pharmaceutical composition for treating a dopamine system disorder in a mammal, comprising administering to said mammal an amount of a selective dopamine receptor D4 compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is effective in treating such disorder. 19. The pharmaceutical composition of claim 18, wherein the dopamine system disorders include psychotic disorders, movement disorders, gastrointestinal disorders, chemical abuse, chemical dependence, substance abuse, vascular and cardiovascular disorders, ocular disorders, and sleep disorders. 20. A pharmaceutical composition for treating a dopamine system disorder in a mammal comprising administering to said mammal an amount of a selective compound. The D4 dopamine receptor of claim 1, or a pharmaceutically acceptable salt thereof, in association with one or more dopamine receptor D1, D2, D3 or DS antagonists, which is effective in treating such a disorder. The pharmaceutical composition of claim 20, wherein the dopamine system disorders include psychotic disorders, movement disorders, gastrointestinal disorders, chemical abuse, chemical dependence, substance abuse, vascular and cardiovascular disorders, ocular disorders and sleep disorders.